pegylated interferon (PEG-IFN) and ribavirin (RBV), a regimen with a hefty price tag that cured barely half of the people who could endure its debilit

Transcription

1 Dear Examiner, According to the provisions of Rule 48 of the Implementing Regulations of the Chinese Patent Law, any person may, from the date of publication of an application for a patent for invention till the date of announcing the grant of the patent right, submit to the patent administration department under the State Council his observations, together with reasons, on the application which is not in conformity with the provisions of the Chinese Patent Law. According to the above provisions, here we, as a third party, are writing to make observations against the following Chinese patent application , entitled Combination formulation of two antiviral compounds (hereinafter referred to as the target application ) which we believe is not patentable in the sense of the Chinese Patent Law and therefore should not be patented. Statement by the third party The submitting third party is Médecins Sans Frontières (MSF), an international, independent, medical humanitarian organisation that delivers medical aid in more than 70 countries to people affected by emergencies, armed conflict, epidemics, natural disasters and exclusion from healthcare. In 1999, in the wake of MSF being awarded the Nobel Peace Prize, MSF launched the Access Campaign, which aims to push for access to, and the development of life-saving medicines, diagnostic tests and vaccines for patients in need. In addition to supporting the effort of the health authorities to improve the access of medicines, diagnostic tests and vaccines; collaborating with the World Health Organisation (WHO) and the manufacturer to reinitiate the production of life-saving medicine which was abandoned by the manufacturer; working with the governments, other international organisations and the manufacturers to search for innovative mechanisms of research and development (R&D) of new treatment for neglected diseases, MSF also improves affordability of medicines through robust generic competition, and has been working on overcoming patent barriers that block access to generic medicines and endanger public health as one of its priorities over the past 18 years. Hepatitis C is a blood-borne virus that can lead to cirrhosis, liver failure and liver cancer, as well as a range of systemic health problems. In 2016, World Health Organization statistics showed an estimated 71 million people have chronic hepatitis C infection worldwide, with 72 per cent living in Low & Middle Income Countries (LMICs). Until 2011, Hepatitis C virus (HCV) was treated with 24 to 48 weeks of 1 / 46

2 pegylated interferon (PEG-IFN) and ribavirin (RBV), a regimen with a hefty price tag that cured barely half of the people who could endure its debilitating and toxic side effects. Since 2011, the emergence of pan-genotypic oral directly-acting antiviral (DAA) medicines has brought hope for patients, with a cure rate of 95 per cent after 12 weeks of treatment. Sofosbuvir (GS-7977) from the US pharmaceutical company Gilead has become the backbone for HCV treatment, used in combination with other DAAs. Sofosbuvir/velpatasvir (GS-5816, i.e. Compound I in the target application) is one of the available pan-genotypic combinations available in a fixed-dose combination, taken as one tablet daily. Such a combination could be an important treatment option in national HCV programs, yet access is limited. Gilead has yet to make sofosbuvir/velpatasvir available in countries in their access programs, and is not yet available in China either. Considering SOF alone, due to high prices in high burden LMICs, evergreening patent strategies and limited territory coverage in Gilead s voluntary license, only 2.1 million people are estimated to have been treated with the new sofosbuvir-based regimens as of the end of 2016, leaving 68.9 million people waiting for access to safer, more tolerable and more effective direct-acting antivirals (DAAs) to treat their HCV. At 8.9 million people, China has the highest total number of people living with chronic hepatitis C virus (HCV) infection in the world. However, the standard treatment for hepatitis C in China is still interferon and ribavirin, largely due to the lack of access to new DAAs for Chinese patients. Gilead has excluded China from its voluntary license territory, thereby barring generic production or importation of generic versions of sofosbuvir or the Active Pharmaceutical Ingredient (API) into the country, which are otherwise already available in other countries such as Malaysia, Thailand, etc. In addition, Gilead has applied for multiple patents on sofosbuvir in China, although many of these do not merit a patent under patentability criteria according to Chinese patent law. Gilead s attempt to secure a monopoly in Chinese market does not only affect China s capacity to provide optimal treatment options for patients in the country, but also limits the possibility for China to produce API or generic sofosbuvir that can be used by patients in China and other countries. In September 2017, the China Food and Drug Administration registered and granted market authorization of sofosbuvir from Gilead. Yet, multiple barriers as above mentioned remain restricting China to get more affordable generic sofosbuvir. In November 2017, Gilead announced the official market launch of sofosbuvir at the price of 58,980 CNY, which is around 8,937 USD per 12-weeks treatment. Together with daclatasvir, Chinese hepatitis C patients will have to pay nearly 80,000 CNY (about 12,000 USD) for the only pan-genotype HCV treatment available in China. However globally, generic competition has already driven the price of this pan-genotypic treatment (sofosbuvir/daclatasvir) down to 120 USD per 12-weeks treatment, more than 1000 times cheaper than the original cost of the treatment using 2 / 46

3 sofosbuvir-based combination, and 100 times cheaper that the launching prices of originators in Chinese market. To overcome patent barriers to access to DAAs in China, non-profit organization I-MAK has filed a third-party observation on the sofosbuvir pro-drug patent application in 2014 (CN A/CN ); and a patent invalidation request on the sofosbuvir base compound patent in 2017 (CN C/CN ). Gilead s patent applications and granted patent claims on sofosbuvir and its combinations with other DAAs have been challenged in many other countries including in India, United States, European Union, Brazil, Russia and Argentina. Following State Intellectual Property Office of China (SIPO) s rejection on the patent application on sofosbuvir prodrug in 2015, on December 4, 2017, Argentina National Institute of Industrial Property (INPI) rejected GILEAD PHARMASSET LLC the same patent application on sofosbuvir prodrug. All of these have been paving the way for improved generic competition, reduced prices and better access for patients. MSF is providing hepatitis C treatment with DAAs to nearly 5,000 patients in 11 countries. The situation of access and generic production at local and global levels would have an impact on MSF s ability to provide better and scaled up treatment for more patients in need. To this end, MSF expects China s capacity of producing Active Pharmaceutical Ingredients (API) and finished final products (FFP) of DAAs, especially sofosbuvir, can be leveraged if unmerited patent barriers are removed. This would have a significant impact on improving accessibility of affordable DAA treatments for the 8.9 million hepatitis C patients in China, and even for untreated patients worldwide. MSF believes that Gilead is trying to undeservedly extend the patent protection of a known medicament with only insignificant modifications, so as to further prevent the public from accessing the medicament, which is against the purpose of legislation of the Chinese Patent Law. MSF hereby submits a third-party observation opposing the grant of a patent on the pending application concerning combination of sofosbuvir and velpatasvir, filed as CN A/CN by Gilead. 3 / 46

4 Basic information of the target application: CN Application No.: CN CN Publication No.: CN A PCT Application No.: PCT/US2014/ PCT Publication No.: WO 2015/ Filing date: January 30, 2014 Priority date (the earliest): August 27, 2013 Applicant: GILEAD PHARMASSET LLC Title of the invention: Combination formulation of two antiviral compounds Throughout the observations, we cite the following reference documents: 1: WO A1, published on May 23, : US A1, published on October 13, : US A1, published on May 2, : US A1, published on October 7, : Food-Effect Bioavailability and Fed Bioequivalence Studies, published in 2002, accessible via the URL 6. NCT on 2013_07_22 (clinical trials), published on July 22, 2013, accessible via the URL Pending claims of the target application (claims of CN A): 1. A pharmaceutical composition comprising: a) an effective amount of a Compound I having the formula: I wherein Compound I is substantially amorphous; and b) an effective amount of sofosbuvir having the formula: 4 / 46

5 wherein the sofosbuvir is substantially crystalline. 2. The pharmaceutical composition of claim 1, wherein Compound I is formulated as a solid dispersion comprising Compound I dispersed within a polymer matrix formed by a pharmaceutically acceptable polymer. 3. The pharmaceutical composition of claim 2, wherein the polymer is hydrophilic. 4. The pharmaceutical composition of claim 2, wherein the polymer is a non-ionic polymer. 5. The pharmaceutical composition of claim 3 or 4, wherein the polymer is hypromellose, copovidone, povidone, or Soluplus. 6. The pharmaceutical composition of claim 5, wherein the polymer is copovidone. 7. The pharmaceutical composition of claim 2, wherein the polymer is an ionic polymer. 8. The pharmaceutical composition of claim 7, wherein the ionic polymer is hydroxypropyl methylcellulose acetate-succinate, hydroxypropyl methylcellulose phthalate, or cellulose acetate phthalate. 9. The pharmaceutical composition of any one of claims 2-8, wherein the weight ratio of Compound I to polymer in the solid dispersion is from about 5:1 to about 1: The pharmaceutical composition of claim 9, wherein the weight ratio of Compound I to polymer in the solid dispersion is from about 2:1 to about 1: The pharmaceutical composition of claim 10, wherein the weight ratio of Compound I to polymer in the solid dispersion is about 1: The pharmaceutical composition of claim 10, wherein the weight ratio of Compound I to polymer in the solid dispersion is about 1:2. 5 / 46

6 13. The pharmaceutical composition of any of the preceding claims, comprising from about 30% to about 70% w/w of sofosbuvir. 14. The pharmaceutical composition of claim 13, comprising from about 35% to about 45% w/w of sofosbuvir. 15. The pharmaceutical composition of claim 14, comprising about 40% w/w of sofosbuvir. 16. The pharmaceutical composition of claim 13, comprising from about 60% to about 70% w/w of sofosbuvir. 17. The pharmaceutical composition of claim 14, comprising about 67% w/w of sofosbuvir. 18. The pharmaceutical composition of any one of claims 2-17, comprising from about 1% to about 45% w/w of the solid dispersion comprising Compound I. 19. The pharmaceutical composition of claim 18, comprising from about 1% to about 25% w/w of the solid dispersion comprising Compound I. 20. The pharmaceutical composition of claim 19, comprising about 1% w/w, about 8% w/w, or about 20% w/w of the solid dispersion comprising Compound I. 21. The pharmaceutical composition according to any one of the previous claims, wherein the crystalline sofosbuvir has XRPD 2θ-reflections at about: (1) 7.5, 9.6, and θ ± 0.2; (2) 5.0, 7.3, and θ ± 0.2; (3) 6.9, 24.7, and θ ± 0.2; (4) 19.7, 20.6, and θ ± 0.2; (5) 5.0, 6.8, and θ ± 0.2; (6) 5.2, 6.6, and θ ± 0.2; or (7) 6.1, 20.1, and θ ± The pharmaceutical composition of claim 21, wherein the crystalline sofosbuvir has XRPD 2θ-reflections at about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20.8, 21.8, and θ ± The pharmaceutical composition of claim 22, wherein the crystalline sofosbuvir has XRPD 2θ-reflections at about: 6.1 and θ ± / 46

7 24. The pharmaceutical composition of any one of the previous claims, further comprising a diluent, a disintegrant, a lubricant, and any combination thereof. 25. The pharmaceutical composition of claim 24, wherein the diluent is selected from the group consisting of dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, lactose, lactose monohydrate, mannitol, microcrystalline cellulose, starch, tribasic calcium phosphate, and combinations thereof. 26. The pharmaceutical composition of claim 25, wherein the diluent is microcrystalline cellulose and is present in an amount from about 5 to about 40% w/w. 27. The pharmaceutical composition of claim 24, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, povidone, pregelatinized starch, sodium starch glycolate, and combinations thereof. 28. The pharmaceutical composition of claim 27, wherein the disintegrant is croscarmellose sodium and is present in an amount from about 1 to about 10% w/w. 29. The pharmaceutical composition of claim 24, wherein the lubricant is selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, and combinations thereof. 30. The pharmaceutical composition of claim 29, wherein the lubricant is magnesium stearate and is present in an amount from about 0.5 to about 3% w/w. 31. The pharmaceutical composition of any one of claims 24-30, comprising: a) about 30 to about 70% w/w of sofosbuvir; and b) about 1 to about 45 %w/w of the solid dispersion comprising Compound I. 32. The pharmaceutical composition of claim 31, comprising a) about 40% w/w of sofosbuvir; and b) about 20% w/w of the solid dispersion comprising Compound I. 33. The pharmaceutical composition of claim 32, further comprising b) about 5 to about 40% w/w microcrystalline cellulose, c) about 1 to about 10% w/w croscarmellose sodium, e) about 0.1 to about 3% w/w magnesium stearate. 7 / 46

8 34. The pharmaceutical composition of claim 31, comprising a) about 67% w/w of sofosbuvir and b) about 8% w/w of the solid dispersion comprising Compound I. 35. The pharmaceutical composition of claim 34, further comprising b) about 5 to about 25% w/w microcrystalline cellulose, c) about 1 to about 10% w/w croscarmellose sodium, e) about 0.1 to about 3% w/w magnesium stearate. 36. The pharmaceutical composition of any one of claims 1-35, wherein the composition is formulated for immediate release. 37. A pharmaceutical dosage form comprising the pharmaceutical composition of any one of the preceding claims, comprising from about 5 to about 450 mg of Compound I. 38. The pharmaceutical dosage form of claim 37, comprising from about 5 to about 150 mg of Compound I. 39. The pharmaceutical dosage form of claim 38, comprising about 100 mg of Compound I. 40. The pharmaceutical dosage form of claim 38, comprising about 25 mg of Compound I. 41. The pharmaceutical dosage form of any one of claims 37-40, comprising from about 200 to about 600 mg of sofosbuvir. 42. The pharmaceutical dosage form of any one of claims 37-40, comprising from about 300 to about 500 mg of sofosbuvir. 43. The pharmaceutical dosage form of any one of claims 37-40, comprising about 400 mg of sofosbuvir. 44. A tablet comprising the pharmaceutical dosage form of any one of claims The tablet of claim 44, further comprising a film coating. 46. The tablet of claim 45, wherein the film coating is a polyvinylalcohol-based coating. 8 / 46

9 47. A method of treating hepatitis C in a human patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of any of claims 1-36, pharmaceutical dosage form of any one of claims 37-43, or a tablet of any one of claims The method of claim 47, wherein the pharmaceutical composition, pharmaceutical dosage form, or tablet is administered for about 12 weeks or less. 49. The method of claim 47, wherein the pharmaceutical composition, pharmaceutical dosage form, or tablet is administered for about 8 weeks or less. 50. The method of claim 47, wherein the pharmaceutical composition, pharmaceutical dosage form, or tablet is administered for about 4 weeks or less. 51. The method of any one of claims 47-50, wherein a sustained virologic response is achieved by about 4 weeks. 52. The method of any one of claims 47-50, wherein a sustained virologic response is achieved by about 12 weeks. 53. The method of any one of claims 47-50, wherein a sustained virologic response is achieved by about 6 months. 54. The method of any one of claims 47-53, further comprising administering an additional therapeutic agent. 55. The method of claim 54, wherein the additional therapeutic agent is ribavirin. 56. A method of treating hepatitis C in a human patient in need thereof comprising administering to the patient a therapeutically effective amount of ribavirin and a therapeutically effective amount of a pharmaceutical composition of any of claims 1-36, pharmaceutical dosage form of any one of claims 37-43, or a tablet of any one of claims 44-46; wherein the ribavirin and pharmaceutical composition, pharmaceutical dosage form, or tablet is administered for about 12 weeks or less. 57. The method of claim 56, wherein the ribavirin and the pharmaceutical composition, the pharmaceutical dosage form, or the tablet is administered for about 8 weeks or less. 58. The method of claim 56, wherein the ribavirin and the pharmaceutical 9 / 46

10 composition, the pharmaceutical dosage form, or the tablet is administered for about 4 weeks or less. 59. The method of any one of claims 47-58, wherein the pharmaceutical composition, pharmaceutical dosage form, or tablet is administrable without regard to food. We believe, based on the above reference documents and common knowledge in the art, none of above claims 1-59 of the target application possesses an inventive step as provided in Article 22, paragraph 3 of the Chinese Patent Law; and claims are non-patentable subject matters as provided in Article 25 of the Chinese Patent Law; detailed reasons for which are provided hereinafter. In the present third-party observations, the expression known in the art and similar expressions means information known before the priority date of the target application. 10 / 46

11 I. Claims 1-46 of the target application do not have an inventive step 1. Claim 1 of the target application seeks to protect a pharmaceutical composition, while Reference D1 (WO A1) discloses a compound for treating HCV, a pharmaceutical composition comprising the compound, and a method for treating HCV by using the compound. D1 discloses that the pharmaceutical composition may further comprise additional therapeutic agent(s) for treating HCV (see for example claim 27 and lines on page 17 of the specification of D1), and the additional therapeutic agent(s) may be a nucleoside or nucleotide inhibitor of HCV NS5B polymerase (see for example claim 29 of D1). In particular, claim 34 of D1, which cites claims 31-33, specifically discloses a pharmaceutical composition comprising: sofosbuvir as the nucleoside or nucleotide inhibitor of HCV NS5B polymerase, and a compound having the following structure:. As can be seen, the above compound in claim 34 of D1 is identical to the Compound I in the target application. That is, the technical solution of claim 34 of D1 discloses a pharmaceutical composition comprising Compound I and sofosbuvir. Therefore, claim 1 of the target application differs from claim 34 of D1 in that 1) Compound I in target claim 1 is substantially amorphous; and 2) sofosbuvir in target claim 1 is substantially crystalline. Based on the above distinguishing features, the technical problem to be solved by target claim 1 is how to provide a pharmaceutical composition comprising Compound I and sofosbuvir which are each in a specific crystalline/amorphous form. However, in a pharmaceutical composition, the active compound(s) being crystalline or amorphous is only a conventional choice in the art. Furthermore, the composition of D1 comprises only two active ingredients, and their possible combinations of crystalline/amorphous forms are very limited. Therefore, the technical solution claimed in target claim 1 is a conventional technical means in the art and would be 11 / 46

12 easily envisaged by a person skill in the art. Moreover, according to the animal experiments on page 232 of D1, Compound I exerts its activity only after being dissolved after administration; and so does sofosbuvir. Therefore, whether they are crystalline or amorphous in the composition would not considerably affect their in vivo therapeutic effect, and the target application does not demonstrate that the combination of the forms of the active ingredients produces any unexpected technical effects. Therefore, claim 1 does not have an inventive step over D1. 2. Claims 2-8 of the target application further define that Compound I is dispersed within a solid polymer matrix, wherein the polymer may be a hydrophilic polymer or a non-ionic polymer such as hypromellose, copovidone, povidone, or Soluplus, or an ionic polymer such as hydroxypropyl methylcellulose acetate-succinate, hydroxypropyl methylcellulose phthalate, or cellulose acetate phthalate. D1 discloses that the compounds of its disclosure (including Compound I) are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice (lines 28-29, page 15 of D1); the excipients include hydroxyalkylcellulose and hydroxyalkylmethylcellulose (line 34, page 15 of D1). D1 further discloses that the active ingredients in the pharmaceutical composition (tablet or aqueous suspension) may be in admixture with non-toxic pharmaceutically acceptable excipient (the last line on page 17 to the first line on page 18, and lines on page 18 of D1), and these excipients may be croscarmellose sodium, povidone, cellulose, microcrystalline cellulose, magnesium stearate (lines 3-6 on page 18 of D1), sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, polyvinylpyrrolidone (i.e. povidone) (lines on page 18 of D1). Among these, povidone and hydroxypropylmethylcellulose are specific examples of a hydrophilic non-ionic polymer. Therefore, the additional technical features of target claims 2-5 are disclosed in D1. Although D1 does not directly disclose copovidone, copovidone is a common excipient in the art. For example, D4 (US A1) uses copovidone as excipient. Since D1 discloses use of povidone and D4 discloses use of copovidone as excipient, it is a conventional technical choice for a person skilled in the art to use copovidone as the excipient for Compound I. Regarding the solid dispersion, for a pharmaceutical purpose, an amorphous active compound present in a solid excipient would certainly form a solid dispersion, which is a conventional choice in the art. For instance, D4 discloses a pharmaceutical 12 / 46

13 composition comprising a solid dispersion of an amorphous compound for treating cystic fibrosis (CF) (see paragraph [0016] of D4), and discloses that the solid dispersion may comprise the polymer copovidone (PVP/VA) (see paragraphs [0025]-[0026] of D4) in which the ratio of the amorphous CF-treating agent to the copovidone may be (20wt% or more):(80wt% or less) (see paragraph [0026] of D4), and the weight percentage of copovidone in the solid dispersion may also be various values in the range from 5% to 99% (see paragraphs [0558]-[0564] of D4). Based on such disclosure, a person skilled in the art would have easily envisaged trying to disperse amorphous Compound I of D1 in a solid matrix of copovidone, and conventionally adjusting the ratio of Compound I to copovidone and their contents. In addition, Example 3 of D4 (see paragraph [0927] of D4) further discloses a tablet, in which copovidone is used in combination with microcrystalline cellulose, sodium croscarmellose, magnesium stearate, etc. as excipients, indicating that these conventional excipients can be used together in combination as excipient. They are essentially the same as the excipients in Table 4 of the target application. Hydroxypropyl methylcellulose acetate-succinate, hydroxypropyl methylcellulose phthalate, or cellulose acetate phthalate are also common excipients and thus conventional choices in the art, and do not bring about any unexpected technical effects for the claimed composition of the target application. In summary, claims 2-8 do not have an inventive step over D1. 3. Claims 9-12 of the target application further define the weight ratio of Compound I to the polymer as 5:1 to 1:5, 2:1 to 1:2, 1:1, or 1:2. First of all, the weight ratio of an active compound to a conventional excipient in a pharmaceutical composition can be routinely adjusted by a person skilled in the art according to actual needs. Furthermore, D1 discloses that the amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration (lines on page 19 of D1); a formulation intended for oral administration to humans may contain a carrier material in an amount of 5% to 95% by weight (see lines on page 19 of D1). D4 also discloses various amounts of copovidone (as excipient) within the range from 5% to 99% (see paragraphs [0026] and [0558]-[0564] of D4). Based on the disclosure of D1 and D4, a person skilled in the art can routinely adjust the weight ratio of an active ingredient (e.g. Compound I) to carrier/excipient (e.g. the polymer matrix) so as to obtain the ratios defined in claims 9-12, which does not need any creative work. And 13 / 46

14 the ratios defined in claims 9-12 do not produce any unexpected technical effects. Therefore, the additional technical features of claims 9-12 are conventional choices in the art, and claims 9-12 do not have an inventive step. 4. Claims of the target application further define that the content of sofosbuvir in the composition is 30% to 70%, 35% to 45%, 40%, 60% to 70%, or 67%. Sofosbuvir is a known anti-hcv drug (see for example D2, D3 or D6), and the composite formulation of sofosbuvir in combination with Compound I has been disclosed in D1. Hence, the content of sofosbuvir in the composite formulation may be routinely adjusted by a person skilled in the art according to practical situations (for example according to conventional parameters in pharmaceutics, such as the therapeutic activity, stability, toxicity, and pharmacokinetic parameters of the composite formulation), which does not require any creative effort. Therefore, the additional technical features of claims are conventional choices in the art, and claims do not have an inventive step. 5. Claims of the target application further define that the content of the solid dispersion comprising Compound I in the composition is 1% to 45%, 1% to 25%, 1%, 8%, or 20%. D1 has disclosed Compound I and the composite formulation of sofosbuvir in combination with Compound I as anti-hcv drugs, and the choice and amount of carrier/excipient for Compound I are also conventional choices (see the comments on claims 2-12). Based on this, the content of the carrier comprising Compound I (i.e. the solid dispersion) in the composite formulation may be conventionally adjusted by a person skilled in the art according to practical situations (for example according to conventional parameters in pharmaceutics, such as the therapeutic activity, stability, toxicity, and pharmacokinetic parameters of the composite formulation), which does not require any creative effort. Therefore, the additional technical features of claims are conventional choices in the art, and claims do not have an inventive step. 6. Claims of the target application further define XRPD parameters of crystalline sofosbuvir. First of all, the XRPD parameters of crystalline sofosbuvir are intrinsic characteristics of crystal forms of sofosbuvir, and do not bring about any unexpected technical 14 / 46

15 effects for the pharmaceutical composition of the target application. Moreover, D2 (US A1) discloses XRPD parameters and spectra of crystals of sofosbuvir (i.e. the S P -4 in D2) (see paragraphs [0102]-[0108] and Figures 3-8 and 21 of D2), wherein: - paragraph [0102] and Figure 3 disclose a crystalline S P -4 having XRPD 2θ-reflections (º) at about 5.2, 7.5, 9.6, 16.7, 18.3, 22.2, which are the same as those in item (1) of claim 21 of the target application; - paragraph [0103] and Figure 4 disclose a crystalline S P -4 having XRPD 2θ-reflections (º) at about 5.0, 7.3, 9.4, 18.1, which are the same as those in item (2) of claim 21 of the target application; - paragraph [0104] and Figure 5 disclose a crystalline S P -4 having XRPD 2θ-reflections (º) at about 4.9, 6.9, 9.8, 19.8, 20.6, 24.7, 25.1 (Figure 5)*, 26.1, which are the same as those in item (3) of claim 21 of the target application; - paragraph [0105] and Figure 6 disclose a crystalline S P -4 having XRPD 2θ-reflections (º) at about 6.9, 9.8, 19.7, 20.6, 24.6, which are the same as those in item (4) of claim 21 of the target application; - paragraph [0106] and Figure 7 disclose a crystalline S P -4 having XRPD 2θ-reflections (º) at about 5.0, 6.8, 19.9, 20.6, 20.9, 24.9, which are the same as those in item (5) of claim 21 of the target application; - paragraph [0107] and Figure 8 disclose a crystalline S P -4 having XRPD 2θ-reflections (º) at about 5.2, 6.6, 7.1, 15.7, 19.1, 25.0, which are the same as those in item (6) of claim 21 of the target application; - paragraph [0108] and Figure 21 disclose a crystalline S P -4 having XRPD 2θ-reflections (º) at about 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20.8, 21.8, 23.3, which are the same as those in item (7) of claim 21, claim 22 and claim 23 of the target application; *NOTE: although paragraph [0104] of D2 does not directly disclose a peak at 25.1º in the XRPD of crystalline S P -4, this peak is distinct and clear around 25.1º in Figure 5 of D2 (see the figure below, wherein the peaks mentioned in paragraph [0104] and the peak at 25.1º are marked by the third party with corresponding 2θ values); furthermore, since paragraph [0049] of D2 discloses that the 2θ values have an error of ±0.2º, a person skilled in the art will be unable to distinguish the crystal of item (3) of claim 21 of the target application from the crystal of Figure 5 of D2. 15 / 46

16 Figure 5 of D2 (the 2θ values of the peaks are marked by us) Therefore, the additional technical features of claims are disclosed in D2. Since the claims referred to by these claims do not have an inventive step, claims also do not have an inventive step. 7. Claims of the target application further define that the pharmaceutical composition further comprise a diluent, a disintegrant, and/or a lubricant, examples thereof, and the contents of some examples thereof. First of all, the diluent(s), disintegrant(s), and lubricant(s) defined in claims are all common excipients/carriers in the art, and are conventional choices of a person skilled in the art that do not require any creative work. And these excipients/carriers do not bring about any unexpected technical effects for the pharmaceutical composition of the target application. Moreover, D1 discloses in lines 27-29, page 17 that the pharmaceutical formulations comprise one or more compounds of the disclosure together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. D1 further discloses in lines 2-6, page 18 that the excipients may be: inert diluents (disclosing a feature of claim 24 of the target application), such as calcium or sodium carbonate, lactose, lactose monohydrate (disclosing features of claim 25), croscarmellose sodium, povidone (disclosing features of claim 27), calcium phosphate (disclosing a feature of claim 25) or sodium phosphate; granulating and disintegrating agents (disclosing a feature of claim 24), such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch 16 / 46

17 (disclosing features of claims 25 and 27), gelatin or acacia; and lubricating agents (disclosing a feature of claim 24), such as magnesium stearate, stearic acid or talc (disclosing features of claim 29). D1 further discloses in lines 14-22, page 18 that the excipients include: a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone (i.e. povidone), gum tragacanth and gum acacia, and dispersing or wetting agents, such as a naturally occurring phosphatide (e.g., lecithin). D1 discloses mannitol and polyethylene glycol as excipients in line 3, page 17 (disclosing features of claims 25 and 29). Seen as such, D1 discloses many technical features of claims 24, 25, 27 and 29. As regards the other examples of excipients not directly disclosed in D1, they are conventional excipients similar to those disclosed in D1, and are conventional choices of a person skilled in the art. As regards the amounts of microcrystalline cellulose, croscarmellose sodium, and magnesium stearate defined in claims 26, 28 and 30 of the target application, these amounts can be obtained by a person skilled in the art by conventional adjustments since these excipients have been disclosed in D1, and such adjustments neither need creative work, nor produce any unexpected technical effects. Furthermore, D4 discloses in Table 3 on pages a tablet containing microcrystalline cellulose, croscarmellose sodium, and magnesium stearate in combination with copovidone as excipient, wherein the amount of microcrystalline cellulose is 27% (disclosing the feature of claim 26 of the target application), the amount of croscarmellose sodium is 3% (disclosing the feature of claim 28 of the target application), and the amount of magnesium stearate is 1% (disclosing the feature of claim 30 of the target application). These not only disclose the additional technical features of claims 26, 28 and 30 of the target application, but also further support that these excipients, their amounts, and their combination, are all conventional choices in the art. In summary, claims of the target application do not have an inventive step. 8. Claims of the target application further define the contents of sofosbuvir and the dispersion of Compound I as well as the contents of microcrystalline cellulose, croscarmellose sodium, and magnesium stearate in the composition of claims With reference to the comments on claims and 24-30, the various amounts defined in claims are merely conventional choices that a person skilled in the art can make based on D1 and/or D4, and do not produce any unexpected technical effects. Therefore, since the claims they refer to do not have an inventive step, claims also do not have an inventive step. 17 / 46

18 9. Claim 36 of the target application further defines that the composition is formulated for immediate release. Pharmaceutical formulations formulated for immediate release, slow release, and controlled release are all conventional choices in the art, and a person skilled in the art can choose any of them according to practical situations. Furthermore, D4 discloses in paragraph [0591] that the tablet comprising a solid dispersion in which the active compound is dispersed in copovidone releases 50%-100% of the active compound within 30 min, which is immediate release. Based on this, a person skilled in the art would have readily envisaged formulating the composition of the target application for immediate release. Therefore, since the claims it refers to do not have an inventive step, claim 36 does not have an inventive step. 10. Claims of the target application claim a pharmaceutical dosage form comprising the pharmaceutical composition of any one of the preceding claims, in which Compound I is about 5 to about 450 mg, about 5 to about 150 mg, about 100 mg, or about 25 mg. D6 (NCT on 2013_07_22) discloses basic information about a Phase II Clinical Trial of the combination of sofosbuvir (SOF) and GS-5816 (i.e. Compound I of the target application, also known as Velpatasvir) for treatment of HCV, and particularly discloses in Arm/Group and Intervention several dosage regimes: SOF 400 mg + 25 mg or 100 mg Compound I, once a day, for 12 weeks. That is, D6 has disclosed the doses of claims In addition, D1 discloses from line 1, page 15 to line 4, page 16 that the compounds (including Compound I of the target application) will be administered in a dose from 0.01 mg to 2 g, about 10 mg to 450 mg, about 25 mg to 250 mg, about 50 mg, or about 100 mg, falling within or overlapping with the ranges defined in claims of the target application. It is a conventional choice of a person skilled in the art to formulate a drug into a dosage form according to its dose to be administered. Therefore, since the claims they refers to do not have an inventive step, claims do not have an inventive step over D1 or over the combination of D1 and D Claims of the target application further define that in the pharmaceutical 18 / 46

19 dosage form sofosbuvir is in an amount of about 200 to about 600 mg, about 300 to about 500 mg, or about 400 mg. First of all, as sofosbuvir is a known anti-hcv drug, its amount in a dosage form may be routinely adjusted according to practical situations. D6 discloses basic information about a Phase II Clinical Trial of the combination of sofosbuvir (SOF) and GS-5816 (i.e. Compound I of the target application, also known as Velpatasvir) for treatment of HCV, and particularly discloses in Arm/Group and Intervention several dosage regimes: SOF 400 mg + 25 mg or 100 mg Compound I. That is, D6 has disclosed the doses of claims In addition, D3 (US A1) discloses in paragraph [0017] that sofosbuvir (GS-7977) was in Phase 2/Phase 3 trials for treatment of chronic HCV infection, and discloses in paragraph [0018] that sofosbuvir was administered at 400 mg for 8 to 12 weeks with or without ribavirin. As can be seen, D3 and D6 disclose the dose of sofosbuvir, either alone or in combination with other anti-hcv agents (such as Compound I), may be 400 mg. Based in such disclosure, a person skilled in the art would be fully motivated to try 400 mg sofosbuvir in a pharmaceutical composition of Compound I and sofosbuvir disclosed in D1, and it is a conventional choice of a person skilled in the art to formulate a drug into a dosage form according to its dose to be administered. Therefore, since the claims they refer to do not have an inventive step, claims do not have an inventive step. 12. Claims of the target application claims a tablet comprising the dosage form, and a tablet comprising a film coating, such as a polyvinylalcohol-based coating. D3 discloses in lines of paragraph [0115] that sofosbuvir (GS-7977) may be administered in tablet form. And a tablet with a film coating and a tablet with a polyvinylalcohol-based coating are common dosage forms in the art, and are conventional choices of a person skilled in the art. The target application fails to show that such tablets produce any unexpected technical effects. Therefore, since the claims they refer to do not have an inventive step, claims do not have an inventive step. II. Claims of the target application have non-patentable subject matters. 19 / 46

20 Claims of the target application claim a method for treating HCV of a human patient, which is directly practiced on a living human body for the purpose of treating a disease (HCV), and is therefore a method for treatment of diseases as stipulated under Article 25 of the Chinese Patent Law. Hence, claims are non-patentable. III. Claims of the target application do not have an inventive step (comments based on assumption) Assuming that the applicant of the target application amends claims into Swiss-type claims, the amended claims would still not have an inventive step. 1. Thus amended claim 47 would claim USE of the pharmaceutical composition of any one of claims 1-36, the dosage form of any one of claims 37-43, or the tablet of any one of claims 44-46, in the manufacture of a medicament for treating HCV in a human patient. D1 describes HCV Combination Therapy on page 21, and discloses in lines on the same page that the compounds of D1 may be combined with ribavirin and/or nucleoside or nucleotide inhibitors of HCV NS5B polymerase for treating HCV. In lines 5-6, page 22, D1 further discloses that the nucleoside or nucleotide inhibitors of HCV NS5B polymerase may be sofosbuvir. Moreover, claim 34 of D1 discloses an anti-hcv pharmaceutical composition comprising the combination of Compound I and sofosbuvir (when referring to claim 33 that refers to claim 31), and discloses an anti-hcv pharmaceutical composition comprising the combination of Compound I, sofosbuvir and ribavirin (when referring to claim 33 that refers to claim 32). Based on the above disclosure of D1, use of the combination of Compound I and sofosbuvir in the manufacture of an anti-hcv medicament is obvious for a person skilled in the art. Therefore, since the claims they refer to do not have an inventive step, amended claim 47 does not have an inventive step. 2. Amended claims further define the period and effect of administration. However, these features are features during administration of the medicament and the therapeutic effect after administration of the medicament, and are not restrictive to the manufacture of the medicament or to the use in the manufacture of the medicament. Hence, these features cannot bring about inventiveness for claim 47, and amended claims do not have an inventive step. 3. Amended claims 54 and 55 further define administration of an additional therapeutic agent which may be ribavirin. These features are disclosed in the section 20 / 46

21 HCV Combination Therapy and claim 34 of D1 (see detailed disclosure above). Therefore, amended claims 54 and 55 do not have an inventive step. 4. Amended claims would claim USE of the pharmaceutical composition of any one of claims 1-36, the dosage form of any one of claims 37-43, or the tablet of any one of claims 44-46, in combination with ribavirin, in the manufacture of a medicament for treating HCV in a human patient (or a similar use), and define the period of administration. The anti-hcv pharmaceutical composition comprising the combination of Compound I, sofosbuvir and ribavirin is disclosed in the section HCV Combination Therapy and claim 34 of D1 (see detailed disclosure above). And the features of the period of administration are not restrictive to the manufacture of the medicament or to the use in the manufacture of the medicament. Therefore, since claims 1-46 do not have an inventive step, amended claims also do not have an inventive step. 5. Amended claim 59 further defines that the pharmaceutical composition, pharmaceutical dosage form, or tablet is administrable without regard to food. The additional technical feature of claim 59 is only a feature about the timing of administration, not restrictive to the manufacture of the medicament or to the use in the manufacture of the medicament, and is merely a conventional parameter in pharmaceutics. Therefore, this feature does not bring about inventiveness for claims 47-58, and amended claim 59 does not have an inventive step. IV. The target application does not record any substantive improvement or unexpected technical effects The target application does not record any substantive improvement on the prior art or any unexpected technical effects that are produced by any technical solution in the specification and claims Example 1-A(i) of the target application describes the dose of sofosbuvir is 400 mg, which is however disclosed in D3 and D6. Example 1-A(ii) of the target application tested doses of Compound I for oral administration and its plasma concentrations after oral administration. However, since Compound I was a known anti-hcv agent, a person skilled in the art would be 21 / 46

22 motivated to test common pharmacokinetic parameters (such as plasma concentration) of the compound, and the corresponding data are easily obtainable through routine means, and an appropriate dose for administration can be selected according to the plasma concentrations, none of which requires any creative work. Furthermore, these doses do not affect claims 1-46 of the target application which do not define the dose to be administered, and these doses are not restrictive to amended (assumed) claims Example 1 s B and C of the target application merely disclose preparation of the solid dispersion and the tablet, which are however all routine operations in the art, and the excipients, their amounts, and their combination are all conventional choices (see e.g. Example 3 of D4, details can be seen above). And Example 1 of the target application does not show that the solid dispersion and the tablet have any unexpected technical effects. 2. Example 2 of the target application describes interaction between sofosbuvir and Compound I, and describes that the plasma exposure of Compound I is not affected by co-administration of sofosbuvir, and the plasma exposure of sofosbuvir increases by about 1.8 times (C max ) and 2.4 times (AUC) when co-administered with Compound I (see paragraph [0256] of the target application CN A). Since D1 has disclosed an anti-hcv composite formulation of the combination of Compound I and sofosbuvir, a person skilled in the art would easily think of routinely testing common pharmacokinetic parameters of the composite formulation (such as the plasma exposure of both active compounds), and these parameters are easily obtainable by routine technical means. The results of these tests are also intrinsic properties of the known composite formulation of D1, which are not unexpected technical effects. Example 2 of the target application further describes that the plasma exposure of sofosbuvir increases by 1.6 times (C max ) and 1.8 times (AUC) when co-administered with the copovidone solid dispersion of Compound I, which are even lower than those values in the above case not using a solid dispersion. This indicates that use of a copovidone solid dispersion of Compound I does not produce any unexpected technical effects. Furthermore, the target application does not show that the above effect in plasma exposure is due to use of amorphous Compound I and/or crystalline sofosbuvir. 3. Example 3 of the target application tested the exposure of Compound I when co-administered with a high-fat/high-calorie meal (HFM), and concludes that the 22 / 46

23 bioavailability of Compound I when co-administered with sofosbuvir increases as compared to administration of Compound I alone. It is well-known in the art that food may affect bioavailability of a drug, see for example D5 (Food-Effect Bioavailability and Fed Bioequivalence Studies, published by FDA in 2002), which discloses that food can alter bioavailability of a drug by various means (see lines 2-9, page 2 of D5), and in general, meals that are high in total calories and fat content are more likely to affect bioavailability of a drug substance or drug product, and thus FDA recommends use of HFM during food-effect bioavailability studies (see lines 14-16, page 2 of D5). Furthermore, an increase or decrease in bioavailability of a drug administered with HFM as compared to administered in a fasted condition is merely a common parameter to determine whether the drug can be administered with or without regard to food (see the 3 rd paragraph to the last paragraph on page 7 of D5), because significantly increased bioavailability upon feeding may increase toxicity while significantly decreased bioavailability upon feeding may reduce activity, and this parameter (increase or decrease in bioavailability) will be used by a person skilled in the art to determine whether food should be considered for administration of the drug, and is per se not an unexpected technical effect. Since D1 has disclosed an anti-hcv composite formulation of the combination of Compound I and sofosbuvir, a person skilled in the art would easily think of routinely testing the effect of HFM on bioavailability of the active ingredients in the composite formulation according to FDA s guideline, and the result is easily obtainable by routine technical means. The result of the test is an intrinsic property of the known composite formulation of D1, which is not an unexpected technical effect. Furthermore, the target application does not show that the above effect is due to use of amorphous Compound I and/or crystalline sofosbuvir. 4. Example 4 of the target application tested the therapeutic effect of the composite formulation of Compound I and sofosbuvir against genotypes 1-6 of HCV. Since D1 and D6 have disclosed use of the composite formulation of Compound I and sofosbuvir for treatment of HCV, and verified the inhibitory effect on genotypes 1-4 of HCV and some of their subtypes (see page 233 of D1), a person skilled in the art would easily think of testing the effect of the composite formulation on other genotypes of HCV, and the result is easily obtainable by routine technical means. The testing result is an intrinsic property of the known composite formulation of D1, which is not an unexpected technical effect. 23 / 46