DETAILED ACTION
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 .
Claim Objections
Claims 29-30 and 33 are objected to because of the following informalities: the last two members of the listed characteristics are not separated by the term “or”. Appropriate correction is required.
Claim Interpretation
Regarding claim 1 and dependent claims thereof, the recitation “characterized by monoclinic syngony” is interpreted by the examiner to be an inherent characteristic of a crystal form of molnupiravir.
Regarding claims 17, 27, and dependent claims thereof, the recitation “exhibiting prophylactic and/or therapeutic antiviral activity” is interpreted by the examiner to be an inherent characteristic of crystal forms of [(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyamino)-2- oxopyrimidin-l-yl]oxolan-2-yl]methyl 2-methylpropanoate (e.g., molnupiravir, EIDD-2801).
Regarding claim 9, the recitation “characterized by the powder…molybdenum K radiation” is interpreted by the examiner to not further limit the crystal form as the recitation does not further limit crystal form of molnupiravir.
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 1-43 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.
The recitation “characterized by monoclinic syngony” renders claims reading upon said recitation indefinite as it is unclear whether the characteristic is inherent to all crystal forms of molnupiravir or if the property is limited to crystal forms of a particular structure. Thus, one would not have been apprised of the metes and bounds of a crystal form of molnupiravir applicant intends to be part of the claimed invention.
Claims 7-8 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.
Regarding claims 7 and 8, the parenthetical phrase “(± 0.2°)” renders the claim indefinite because it is unclear whether the limitations within the parentheses are part of the claimed invention. See MPEP § 2173.05(d).
Claim 39 is 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.
The term “mild” in claim 39 is a relative term which renders the claim indefinite. The term “mild” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Thus, one would not have been apprised of the metes and bounds of a medicament that applicant intends to be part of the claimed invention.
Claims 41-43 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.
The claims are indefinite because the claims fail to set forth an active methodological step(s).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 41-43 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because “use” is not a process, machine, manufacture, or composition of matter, or a new and useful improvement thereof.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 9-11, and 15-16 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Paymode, Dinesh J., et al. "Toward a practical, two-step process for molnupiravir: Direct hydroxamination of cytidine followed by selective esterification." Organic Process Research & Development 25.8 (2021): 1822-1830 (Paymode).
Paymode teaches that molnupiravir (also known as EIDD-2801 and MK-4482) is emerging as a drug candidate of increasing interest based on its potential to treat COVID-19 (page 1). Molnupiravir showed broad spectrum antiviral activity against SARS-CoV-2 with reduced virus titer in mice,1 and completely blocked SARS-CoV-2 transmission in ferrets within 24 hr of administering the medication. From a pragmatic standpoint, molnupiravir is orally available and is structurally simple compared to remdesivir, making future manufacture considerably less complex.
Paymode teaches that selection of water as a crystallization solvent for crude reaction mass returned material of excellent quality, and water did not cleave the ester to an appreciable extent (page 7).
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Paymode teaches a crystal form of molnupiravir having a purity of 99.4% (Fig. 14).
Paymode teaches all of the instantly claimed elements. Thus, claims 1, 9-11, and 15-16 anticipated.
Claim(s) 41 and 43 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Paymode, Dinesh J., et al. "Toward a practical, two-step process for molnupiravir: Direct hydroxamination of cytidine followed by selective esterification." Organic Process Research & Development 25.8 (2021): 1822-1830 (Paymode) as applied to claims 1, 9-11, and 15-16 above.
Paymode teaches a crystal form of molnupiravir. Paymode further teaches the use of molnupiravir to treat COVID-19.
Paymode teaches all of the instantly claimed elements. Thus, claims 41 and 43 are anticipated.
Claim(s) 1, 9-10, 17, 20, 22-27, and 39 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nanjing Zhengji Pharmaceutical Research Co ltd. CN 113072606 A (Nanjing Zhengji).
Nanjing Zhengji provides crystalline forms of the compound of formula (1) and methods of making the same, including crystalline forms I, III, and IV thereof (Abstract). The crystal form provided by the disclosure has good stability and clinical application value.
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Nanjing Zhengji teaches that, preferably, the compound of the formula (1) in the crystal form I has diffraction peaks at the X-ray powder diffraction spectrum 2 theta values of 3.34 +/-0.2 degrees, 6.60 +/-0.2 degrees, 13.17 +/-0.2 degrees, 16.47 +/-0.2 degrees, 17.30 +/-0.2 degrees, 18.23 +/-0.2 degrees, 19.66 +/-0.2 degrees, 20.68 +/-0.2 degrees, 28.25 +/-0.2 degrees and 28.96 +/-0.2 degrees. See page 2.
The pharmaceutical composition of Nanjing Zhengji comprises compound of formula (1) form I, form III or form IV, and a pharmaceutically acceptable carrier, diluent or excipient. See page 6. Nanjing Zhengji also provides the use of a compound of formula (1) form I, form III or form IV, or a pharmaceutical composition comprising the foregoing forms, in the manufacture of a medicament for the treatment of an infection such as, but not limited to, eastern equine encephalitis, western equine encephalitis, venezuelan equine encephalitis, Ebola, influenza, coronavirus, or zika virus.
Nanjing Zhengji teaches all of the instantly claimed elements. Thus, claims 1, 9-10, 17, 20, 22-27, and 39 are anticipated.
Claim(s) 41-43 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nanjing Zhengji Pharmaceutical Research Co ltd. CN 113072606 A (Nanjing Zhengji) as applied to claims 1, 9-10, 17, 20, 22-27, and 39 above..
Nanjing Zhengji teaches the use of a crystalline form of molnupiravir to treat viral infections such as Ebola.
Nanjing Zhengji teaches all of the instantly claimed elements. Thus, claims 41-43 are anticipated.
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 11, 18-19, 21, and 28-40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nanjing Zhengji Pharmaceutical Research Co ltd. CN 113072606 A (Nanjing Zhengji) as applied to claims 1, 9-10, 17, 20, 22-27, 39, and 41-43 above, and further in view of Roberts et al. US 5,905,082 (Roberts).
Nanjing Zhengji differs from the instantly claimed invention in that Nanjing Zhengji does not 1) explicitly teach a composition comprising a crystal form of molnupiravir formulated into a powder, tablet, capsule, film-coated tablet, solution, syrup, parenteral injection, aerosol, rectal medicament, etc. and does not 2) explicitly teach a composition comprising an instantly claimed amount of molnupiravir such as 20 to 6000 mg; however, these deficiencies would have been obvious in view of the teachings of Roberts.
In the instant case, the references may be combined to show obviousness because Nanjing Zhengji and Roberts are each drawn to crystalline nucleosides useful for the treatment of viral infections. They are from the same field of endeavor, and/or are reasonably pertinent to a crystal form of molnupiravir.
Roberts is concerned with 1,3-oxathiolane nucleoside analogues, particular physical form thereof, pharmaceutical formulations thereof and the use thereof in the treatment of viral infections (column 1, lines 4-9). In a further aspect there is provided 3TC in the form of bipyramidal crystals (column 2, lines 51-52. Roberts teaches while it is possible that, for use in therapy, the bipyramidal crystalline compound of the invention may be administered as the raw chemical it is preferable to formulate it into a pharmaceutical formulation (column 4, lines 25-28).
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation (column 4, lines 37-65). The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and the, if necessary, shaping the product into the desired formulation.
Pharmaceutical formulations suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution, a suspension or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives. For administration by inhalation the bipyramidal crystal line compound according to the invention is conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray (column 5, lines 49-58).
In determining the differences between the prior art and the claims, the question under 35 U.S.C. 103 is not whether the differences themselves would have been obvious, but whether the claimed invention as a whole would have been obvious. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 218 USPQ 871 (Fed. Cir. 1983); Schenck v. Nortron Corp., 713 F.2d 782, 218 USPQ 698 (Fed. Cir. 1983).
It would have been obvious to provide the crystal form of molnupiravir disclosed by Nanjing Zhengji in a conventional pharmaceutical formulation such as a powder, film-coated tablet, solution, aerosol, or rectal medicament. One would have been motivated to do so to protect the active agent from stomach acid, control how fast the body absorbs the active agent, ensure exact dosing, and/or to make the active agent stable. One would have had a reasonable expectation of success as Roberts teaches the formulation of crystalline forms of a nucleoside drug into a powder, film-coated tablet, solution, aerosol, rectal medicament, and the like. Regarding the instantly claimed amount(s), the amount(s) could have been obtained via routine experimentation as molnupiravir was known to have antiviral activity (e.g., a result effective variable).
Routine experimentation in the field of antiviral pharmaceuticals is exemplified by Gish, R. G., et al. "Dose range study of pharmacokinetics, safety, and preliminary antiviral activity of emtricitabine in adults with hepatitis B virus infection." Antimicrobial agents and chemotherapy 46.6 (2002): 1734-1740 (Gish). Gish teaches that a multicenter, open-label study was performed to evaluate the safety, anti-hepatitis B virus (anti-HBV) activity, and pharmacokinetics of emtricitabine therapy administered once daily for 8 weeks to patients infected with HBV (Abstract). Clinical and virologic evaluations were completed at the baseline; at 7, 14, 28, 42, and 56 days during treatment; and at 24, 48, and 28 days posttreatment. Forty-nine patients were enrolled in five dose cohorts (doses of 25, 50, 100, 200, and 300 mg, all of which were administered once daily [q.d.]). Peak plasma emtricitabine concentrations occurred within 1.5 h following dosing. Plasma emtricitabine concentrations (maximum concentrations of drug in plasma and areas under the concentration-time curves) increased nearly dose proportionally over the 25- to 300-mg dose range, with relatively small intersubject variabilities. The plasma half-life of emtricitabine ranged from 6 to 9 h. HBV DNA levels were measured by the Digene HBV Hybrid Capture II assay. Viral suppression (reduction in log10 serum HBV DNA levels) occurred in all dose cohorts.
All of the instant limitations are taught by the combination of Nanjing Zhengji and Roberts. A person of ordinary skill in the art would have had a reason to combine the teachings of Nanjing Zhengji and Roberts. A person of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Nanjing Zhengji and Roberts. Thus, claims 11, 18-19, 21, and 28-40 would have been obvious based on the preponderance of the evidence.
Conclusion
Claims 1-43 are pending. Claims 1-43 are rejected. No claims are allowed.
Contacts
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PATRICK T LEWIS whose telephone number is (571)272-0655. The examiner can normally be reached Monday to Friday, 10 AM to 4 PM EST (Maxi Flex).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PATRICK T LEWIS/Primary Examiner, Art Unit 1691
/PL/
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