Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Amended claim 1, and new claims 14-20 are pending. The amendments render the restriction requirement moot.
Claims 1, 14-20 are examined together.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chal US 20140212491, Franciscus HCSP, version 1, June 2014, pages 1-3 and Poole Drugs, 2014, 74, pages 1559-1571 all of record further in view of Xiao, Gut 2015;64:483–494, Published Online First 21 May 2014, Guedja PNAS 2013 vol. 110 no. 10, 3991–3996 and Lawitz N Engl J Med 2013;368:1878-87.
Instant Claims:
10. (Currently Amended) A method for treating a hepatitis C viral (HCV) infection to achieve a rapid initial viral response infections, comprising: administering an effective amount of sofosbuvir, daclatasvir, and simeprevir to a subject in need thereof.
14. (New) The method of claim 10 wherein 400 mg of sofosbuvir is administered once daily, 60 mg of daclatasvir is administered once daily, and 150 mg of simeprevir is administered once daily.
Claim 10:
Chal teaches the combination of ledipasvir and sofosbuvir (claim 1) for the treatment of hepatitis C (claim 75) for 24 weeks or less (claims 76-69) for the genotype 1a or 1b (claims 83-84). Chal teaches further comprising simeprevir (claim 93). Chal teaches that the pharmaceutical dosage form comprises about 40, or about 45, or about 50, or about 55, or about 60, or about 70, or about 80, or about 100, or about 120, or about 140, or about 160, or about 180, or about 200, or about 220 mg of ledipasvir (paragraph 0115). Chal teaches that the pharmaceutical dosage form comprises from about 1 to about 800 mg, or about 100 to about 700 mg, or about 200 to about 600 mg, or about 300 to about 500 mg, or about 350 to about 450 mg, of sofosbuvir. (paragraph 0116). Chal teaches that the daily dose is 90 mg of ledipasvir and 400 mg of sofosbuvir administered in the form of a tablet (paragraph 0126). Chal teaches that further HCV agents may be included such as daclatasvir, simeprevir and asunaprevir (paragraph 0149-0151). Chal teaches that the term “sustained virologic response' refers to the absence of detectable RNA (or wherein the RNA is below the limit of detection) of a virus (i.e. HCV) in a patient sample (i.e. blood sample) for a specific period of time after discontinuation of a treatment. For example, a SVR at 4 weeks indicates that RNA was not detected or was below the limit of detection in the patient at 4 weeks after discontinuing HCV therapy (paragraph 0042). Chal teaches that throughout treatment, HCV RNA was measured, and the Sustained Virologic Response (SVR) was measured after treatment was discontinued. By four weeks of treatment, almost all patients had achieved an HCV RNA measurement below the limit of detection (LOD of 15 IU/mL) (e.g. cure). and by the end of treatment, 100% of patients achieved an HCV RNA level below the LOD (Table 14). Chal teaches that in some embodiment that the treatment of HCV is about 4 weeks or less (paragraph 0124). Chal teaches some embodiments, the patient is also suffering from cirrhosis. And yet a further embodiment, the patient is not suffering from cirrhosis (paragraph 0127). Chal teaches the measurement of base line HCV RNA (paragraph 0208-210, 0244). Chal teaches that the composition are effective in treating genotype 1 HCV infected patients, including genotype 1a and/or genotype 1b (paragraph 0123). Chal teaches oral administration throughout the publication and in examples.
Claim 14:
Chal does not teach specifically the dosage of daclatasvir, simeprevir or asunaprevir. HCSP teaches sofobuvir is a 400 mg pill taken once-a-day. And simeprevir is a 150 mg take once-a-day (page 2). Poole teaches than the approved dosage of the combination is daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily (page 1560, left column). It would have been obvious to one of ordinary skills in the art at the time of filing to combine in any combination of sofobuvir, simeprevir, daclatasivir and asunaprevir to effectively treat hepatitis C viral infection. One would have been motivated to combine in any combination of sofobuvir, simeprevir, daclatasivir and asunaprevir to effectively treat hepatitis C viral infection because it is known in the art that combinations of sofobuvir, simeprevir, daclatasivir and asunaprevir is effective in the treatment of HCV within four weeks of treatment as disclosed by Chal, HCSP and Poole with a reasonable expectation of success absence evidence to the contrary. It would have been obvious to one of ordinary skills to combine HCV agents with a JAK inhibitor for the treatment of HCV. As stated in In re Kerkhoven, 626 F.2d 846, 205 USPQ 1069, at page 1072 (CCPA 1980): It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (CCPA 1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art. Therefore, it would have been prima facie obvious to combine sofobuvir, simeprevir, daclatasivir and/or asunaprevir and JAK inhibitor composition cojointly in a formulation to treat HCV infection with a reasonable expectation of success. The amounts of active agents to be used, the pharmaceutical forms, e.g., tablets, etc; mode of administration, flavors, surfactant are all deemed obvious since they are all within the knowledge of the skilled pharmacologist and represent conventional formulations and modes of administration. Furthermore, it is obvious to vary and/or optimize the amount of sofobuvir, simeprevir, daclatasivir and asunaprevir provided in the composition, according to the guidance provided by Chal, HCSP and Poole, to provide a composition having the desired properties such as the desired (ratios, concentrations, percentages, etc.). It is noted that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
The limitation of ‘rapid initial viral response’:
(The significance of this limitation is apparent in the context of what are in the file-wrapper for the originally filed application and its CON)
Xiao Guedja and Lawitz are invoked for this limitation.
Xiao teaches synergy of entry inhibitors with direct-acting antivirals uncovers novel combinations for prevention and treatment of hepatitis C. Xiao at page 488 column B, teach that treatment of HCV-infected cells simeprevir, resulted in a rapid reduction of viral load in a time dependent manner. However, an increase in viral load was observed following withdrawal of simeprevir. In contrast, the addition of an entry inhibitor (anti-CD81 mAb or erlotinib) at the time of simeprevir withdrawal allowed to further decrease the viral load, indicating that entry inhibitors limit viral rebound. It is one of commonsense that viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. While it is acknowledged that the above noted antibody or erlotinib is not one of the combinations, the benefit of ‘rapid response’ in the treatment of HCV is not outside the purview of one of skill in the art. See Guedja, page 3991 column B, lines 3-5. According to Guedja page 3991 column A, first highlighted paragraph. daclatasvir treatment led to an immediate and rapid decline of extracellular HCV titers compared to a delayed (6–9 h) and slower decline with NM107, confirming an effect of daclatasvir on both viral replication and assembly/secretion and at page 3992, column A, line 4-6, patients treated with 10 or 100 mg of daclatasvir had a profound and rapid HCV RNA decline; also at page 3994, last paragraph Guedja teaches that after in vivo administration of the daclatasvir, HCV RNA declines with extreme rapidity. Likewise, Lawitz teaches at page 1881, last paragraph line 1, that all patients receiving sofosbuvir in the two studies had rapid and substantial decreases in serum HCV RNA levels.
For these reasons, the claimed subject matter is deemed to fail to be patentably distinguishable over the state of the art as represented by the cited reference. The claims are therefore, properly rejected under 35 U.S.C. 103.In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Therefore, one of skill in the art would have reasonable expectation of success in arriving at the recited combination for rapid initial viral response.
As such there is nothing unobvious in the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 15-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 15-20 dependent on a non-existent claim 12. As such what the method of these claims entail is unclear.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625