FINAL REJECTION
Receipt is acknowledged of Applicants' Amendments and Remarks, filed Jun. 30, 2026.
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The rejections and/or objections set forth below are either maintained or newly applied, and constitute the complete set presently applied to the instant claims.
STATUS OF THE CLAIMS
No claims have been canceled, and no new claims have been added.
Claim 6 stands withdrawn as drawn to nonelected inventions and/or species.
Thus, claims 1-5 and 7-20 now represent all claims currently pending and under consideration.
INFORMATION DISCLOSURE STATEMENT
No new Information Disclosure Statements (IDS) have been submitted.
MAINTAINED REJECTIONS
The following rejection is maintained from the previous Office Action dated Oct. 30, 2025, on the ground that the references cited therein continue to read on the limitations of the amended claims.
Claim Rejections - 35 U.S.C. § 102
Claims 1-5 stand rejected under 35 U.S.C. 102(a)(2) as being anticipated by Bonnac et al. (US Pub. 2022/0273689).
Bonnac et al. claim methods of treating an RNA virus infection comprising administering a combination of therapeutically effective amounts of (i) an antiviral nucleobase or a pharma-ceutically acceptable salt thereof; and (ii) a de novo nucleotide biosynthesis inhibitor (DNNBi) or a pharmaceutically acceptable salt thereof (claim 1).
The RNA virus infection is, e.g., severe acute respiratory syndrome (SARS) virus, Middle East Respiratory syndrome (MERS) coronavirus, SARS-CoV-2, respiratory syncytial virus, or influenza A (claim 2).
The de novo nucleotide biosynthesis inhibitor (DNNBi) is selected from a folate synthesis inhibitor, e.g., pemetrexed (claim 9).
Thus, Bonnac et al. disclose and claim methods of treating viral pulmonary infections caused by a coronavirus, e.g., SARS coronavirus, comprising administering a therapeutically effective amount of an antifolate, e.g., pemetrexed, as recited by claims 1-5.
As evidenced by the instant specification (p. 14, line 5 to p. 15, line 1), pemetrexed has the structure of formula (II), as recited by claim 3:
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which reads on formula (I) as recited by claim 2, wherein X is CH; R1 is hydrogen; and R2 is
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As noted above, Bonnac et al. disclose and claim administering pemetrexed as the de novo nucleotide biosynthesis inhibitor (DNNBi), or a pharmaceutically acceptable salt thereof, as recited by claim 4.
For the foregoing reasons, Bonnac et al. anticipates claims 1-5.
Claim Rejections - 35 U.S.C. § 103
Claims 1-5 and 7-20 stand rejected under 35 U.S.C. 103 as being unpatentable over Bonnac et al. (US Pub. 2022/0273689) in view of Mandal et al. (US Pub. 2017/0340639).
Bonnac et al. claim methods of treating an RNA virus infection comprising administering a combination of therapeutically effective amounts of (i) an antiviral nucleobase or a pharmaceutically acceptable salt thereof; and (ii) a de novo nucleotide biosynthesis inhibitor (DNNBi) (DNNBi) or a pharmaceutically acceptable salt thereof (claim 1).
The RNA virus infection is, e.g., severe acute respiratory syndrome (SARS) virus, Middle East Respiratory syndrome (MERS) coronavirus, SARS-CoV-2, respiratory syncytial virus, or influenza A (claim 2).
The de novo nucleotide biosynthesis inhibitor (DNNBi) is selected from a folate synthesis inhibitor, e.g., pemetrexed (claim 9).
Thus, Bonnac et al. disclose and claim methods of treating viral pulmonary infections caused by a coronavirus, e.g., SARS coronavirus, comprising administering a therapeutically effective amount of an antifolate, e.g., pemetrexed, as recited by claims 1-5.
As evidenced by the instant specification (p. 14, line 5 to p. 15, line 1), pemetrexed has the structure of formula (II), as recited by claim 3:
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which reads on formula (I) as recited by claim 2, wherein X is CH; R1 is hydrogen; and R2 is
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As noted above, Bonnac et al. disclose and claim administering pemetrexed as the de novo nucleotide biosynthesis inhibitor (DNNBi), or a pharmaceutically acceptable salt thereof, as recited by claim 4.
The compositions of Bonnac et al. are disclosed for suitable routes of administration, e.g., parenterally, including subcutaneous, intramuscular, intravenous, intradermal, etc.; and where the compound is administered parenterally, it may be formulated in a unit dosage injectable form (para. [0128]), which reads on parenteral administration by intravenous (IV) injection, as recited by claims 7 and 8.
Bonnac et al. disclose that suitable aqueous solvents include, e.g., water, (para. [0125]), implicitly disclosing formulations in the form of an aqueous solution, as recited by claim 13.
Bonnac et al. disclose that a dose to treat human patients may range from about 1 mg to about 2000 mg of DNNBi (i.e., pemetrexed) (para. [0129]), which encompasses the dosages recited by claims 9, 10, and 18-20.
Bonnac et al. differs from the instant claims in that the reference does not disclose the specific components, amounts, and/or dosages recited by claims 9-20.
However, pharmaceutical compositions comprising pemetrexed together with the claimed excipients were known in the art.
Mandal et al. disclose liquid ready-to-use injections comprising pemetrexed (abstract), in a concentration of 5-100 mg/ml (para. [0021]), comprising water for injection as a vehicle (para. [0033]), i.e., in the form of an aqueous solution, as recited by claim 13.
It is implicit in a "ready-to-use" injection that the route of administration is via intravenous bolus injection, as recited by claims 8, 16, and 17.
Mandal et al. exemplify formulations comprising pemetrexed at a concentration of 10 mg/ml (Examples 1-5; claim 20), and 1.0 mg/ml sodium disulfite (Example 4).
Mandal et al. further exemplify pemetrexed formulations comprising L-cysteine hydrochloride (para. [0145]); and disclose pemetrexed formulations comprising L-cysteine (claim 13) and sodium sulfite (para. [0018]; claim 14), as recited by claims 11, 12, and 14.
Therefore, it would have been predictable to one of ordinary skill in the art as of the filing date to prepare the compositions of Bonnac et al. with the excipients disclosed by Mandal et al. with a reasonable expectation of success, because Mandal et al. demonstrate that pemetrexed is stable and compatible in compositions with cysteine hydrochloride and sodium sulfite.
The cited references differ from the instant claims in that the references do not specify the exact amounts of the components in the claimed formulations:
comprising about 2 % w/w to about 10 % w/w of antifolate, 0.04 % w/w to about 0.2 % w/w cysteine hydrochloride monohydrate, and 0.1 % w/w to about 0.95 % w/w sodium sulfite, as recited by claim 14, or
wherein the osmolality of the formulation is from about 250 mOsm to about 400 mOsm, as recited by claim 15;
or pemetrexed dosages in the amount of:
from about 0.01 mg/m2 to about 700 mg/m2 of body surface area, as recited by claim 9;
from about 0.2 mg to about 300 mg, as recited by claim 10;
from about 0.1 mg/m2 to about 150 mg/m2 of body surface area, as recited by claim 18;
from about 25 mg/m2 to about 100 mg/m2 of body surface area, as recited by claim 19; or
from about 35 mg/m2 to about 75 mg/m2 of body surface area, as recited by claim 20.
However, the cited references disclose compositions comprising each of the claimed components, and the administration of pemetrexed in therapeutic amounts.
For treating pulmonary viral infections in human patients, Bonnac et al. disclose a dosage range from about 1 mg to about 2000 mg of antiviral nucleobase compound, and about 1 mg to about 2000 mg of DNNBi (e.g., pemetrexed). The doses may be administered once a day (QD), twice per day (BID), or more frequently, depending on the pharmacokinetic (PK) and pharmacodynamic (PD) properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors may influence the dosage and administration dosing regimen (para. [0129]).
Therefore, it would have been predictable to an ordinarily skilled clinician as of the filing date to optimize the effective dosage of DNNBi (e.g., pemetrexed) of about 1 mg to about 2000 mg as disclosed by Bonnac et al. to arrive at the claimed dosages with a reasonable expectation of success, because the antiviral dose of pemetrexed is a result-effective variable which determines the therapeutic outcome and can be optimized by routine experimentation.
Further, "the normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of ranges is the optimum combination of percentages." In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382.
As recognized by MPEP § 2144.05,
Generally, differences in concentration or tempera-ture will not support the patentability of subject mat-ter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to dis-cover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
RESPONSE TO ARGUMENTS
Applicant's arguments filed Jun. 30, 2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. §§ 102 and 103, Applicant argues that Bonnac et al. does not disclose administering "a therapeutically effective amount of an antifolate" as required by claim 1.
Applicant contends that the entire technical disclosure of Bonnac is directed to a combination therapy, where the active agent for treating the virus is an antiviral nucleobase, which is used in combination with a de novo nucleotide biosynthesis inhibitor (DNNBi). While the DNNBi may be an antifolate such as pemetrexed, the antifolate is administered as a non-therapeutic potentiator or helper molecule to promote the metabolic conversion of the nucleobase, not as a therapeutic agent effective on its own.
Applicant argues that Bonnac teaches that the DNNBi (antifolate) is not administered in an amount that is individually therapeutically effective to treat the virus. The experimental data in Bonnac demonstrates that when the DNNBi is administered alone at the disclosed concentrations, it exhibits no or negligible antiviral activity. For example, paragraph [0114] of Bonnac states, with respect to the DNNBi 6-MMPR: “also striking is the lack of antiviral activity for 6-MMPR alone at 0.01 µM demonstrating that neither compound alone is effective.”
Thus, Applicant argues that Bonnac teaches the opposite of what is claimed: Bonnac only discloses administering an antifolate (i.e., DNNBi) in combination with a nucleobase, and specifically teaches that the antifolate is ineffective when administered alone at those concentrations. Accordingly, Bonnac does not disclose administering "a therapeutically effective amount of an antifolate" as required by claim 1 (Remarks, pp. 2-3).
It is acknowledged that Bonnac et al. is directed to a combination therapy: an antiviral nucleobase in combination with a de novo nucleotide biosynthesis inhibitor (DNNBi), which includes antifolates. However, Applicant’s reading of the reference is overly restrictive.
In fact, Bonnac et al. disclose that neither active agent alone – neither the antiviral nucleobase, nor the DNNBi (antifolate) – is effective at the tested concentrations; but the combination of the two together is effective (para. [0114]):
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Further, Bonnac et al. demonstrate that the combination of the two compounds is synergistic, which are administered in synergistic amounts (paras. [0029], [0109], [0114]; Figs. 4A-C, 6A, 6B, 8A-C, 9A, 9C, 10A, 10B, 11B). Bonnac et al. define the term "synergistic" as a therapeutic combination which is more effective than the additive effects of the two or more single agents (para. [0071]).
Thus, Bonnac et al. do not disclose the DNNBi (antifolate) as merely a non-therapeutic potentiator or helper molecule to promote the metabolic conversion of the nucleobase: Fig. 12 is a diagram showing the cooperative mechanism of the combination, both of which contribute to the antiviral effect (para. [0120]):
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In addition, Bonnac et al. claim a method for the treatment of an RNA virus infection comprising administering a therapeutic combination comprising therapeutically effective amounts of (i) an antiviral nucleobase or a pharmaceutically acceptable salt thereof; and (ii) a de novo nucleotide biosynthesis inhibitor (DNNBi) or a pharmaceutically acceptable salt thereof (claim 1). The use of the term “amounts,” plural, expressly contemplates the administration of a therapeutically effective amount of each of the two compounds: (1) a therapeutically effective amount of an antiviral nucleobase, and a therapeutically effective amount of a de novo nucleotide biosynthesis inhibitor (DNNBi).
Bonnac et al. (para. [0063]) define "therapeutically effective amount" as:
an amount of a compound that (i) treats the particular infection, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular infection, or (iii) prevents or delays the onset of one or more symptoms of the particular infection described herein. Furthermore, "therapeutically effective amount" is an amount of a drug that is low enough to be non-toxic, yet sufficient to achieve a therapeutic result, including eliminating, reducing, and/or slowing the progression of a condition or symptom thereof. The therapeutically effective amount may depend on biological factors. Achieving a therapeutic result can be measured by physician or other qualified medical personnel using objective evaluations known in the art, or it can be measured by individual, subjective patient assessment.
This is similar to the definition of “therapeutically effective amount” set forth in the specification (p. 7, lines 18-24):
The term “effective amount” or “therapeutically effective amount” refers to the amount of antifolate described herein that is sufficient to achieve the effect of the intended application including, but not limited to, disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
Thus, Bonnac et al. explicitly disclose and claim methods of administering a therapeutically effective amount of an antifolate, as required by claim 1.
In addition, the instant claims are drawn to methods of treating a viral pulmonary infection, comprising administering to a subject in need thereof a therapeutically effective amount of an antifolate. Thus, the claimed methods do not exclude the administration of a second active agent together with the antifolate.
As recognized by MPEP §2111.03, the transitional term “comprising,” which is syn-onymous with “including,” “containing,” or “charac-terized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) (“like the term ‘comprising,’ the terms ‘containing’ and ‘mixture’ are open-ended.”). Invitrogen Corp. v. Biocrest Mfg., L.P., 327 F.3d 1364, 1368, 66 USPQ2d 1631, 1634 (Fed. Cir. 2003) (“The transition ‘com-prising’ in a method claim indicates that the claim is open-ended and allows for additional steps.”); Genen-tech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997) (“Comprising” is a term of art used in claim language which means that the named elements are essential, but other ele-ments may be added and still form a construct within the scope of the claim.); Moleculon Research Corp. v. CBS, Inc., 793 F.2d 1261, 229 USPQ 805 (Fed. Cir. 1986); In re Baxter, 656 F.2d 679, 686, 210 USPQ 795, 803 (CCPA 1981); Ex parte Davis, 80 USPQ 448, 450 (Bd. App. 1948) (“comprising” leaves “the claim open for the inclusion of unspecified ingredi-ents even in major amounts”).
With respect to the rejection under 35 U.S.C. § 103 over Bonnac et al. in view of Mandel et al., Applicant argues that Mandal does not cure the deficiency of Bonnac: Mandal is strictly directed to optimizing the chemical stability of ready-to-use liquid anti-neoplastic pemetrexed formulations by controlling dissolved oxygen levels and utilizing antioxidants. Mandal provides no teachings whatsoever regarding viral infections, antiviral therapies, or clinical administration protocols for treating viral pulmonary infections. Mandal is concerned only with formulation stability for oncology applications (Remarks, p. 3).
Thus, Applicant argues that a person of ordinary skill in the art would not have been motivated to combine Bonnac and Mandal to arrive at the presently claimed method. Even if one were to artificially combine the references, the result would merely be a stable liquid formulation of Bonnac's combination therapy, where the antifolate acts as a non-therapeutic potentiator to an antiviral nucleobase. The combination of Bonnac and Mandal would not lead the skilled person to the claimed method of administering a therapeutically effective amount of an antifolate to treat viral pulmonary infections (Remarks, p. 3).
However, as discussed in the rejection set forth above, Mandal et al. is cited for its teachings of compositions comprising pemetrexed together with the claimed excipients,
regardless of their intended use.
For the foregoing reasons, the rejections under 35 U.S.C. §§ 102 and 103 are maintained.
CONCLUSION
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
CORRESPONDENCE
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 10:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. Lundgren, can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARA E. TOWNSLEY/Examiner, Art Unit 1629
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