DETAILED ACTION
The preliminary amendment submitted on August 8, 2024 has been entered. Claims 1-23, 25, 29-37, 39-45, 60, 87-88, 90, and 95-96 are pending in the application and are rejected for the reasons set forth below. No claim is allowed.
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 . 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.
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.
Claims 1-23, 25, 29-37, 39-45, 60, 87-88, 90, and 95-96 rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The claims include contingent limitations. Specifically, they provide for a situation “if the patient misses or will miss a maintenance dose,” but it is unclear whether the claims read on the opposite situation. “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met.” See MPEP1 2111(II) (contingent limitations).
The claims are given their broadest reasonable interpretation during examination. There-fore, the following limitations have not been accorded patentable weight because they are optional:
wherein if the patient misses or will miss a maintenance dosage …, the method further comprises orally administering to the patient a bridging dosage of about 250 mg to about 650 mg of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, once per week until the patient resumes administration of the one or more maintenance dosages
See the end of claims 1 and 29-30, respectively. These contingent limitations appear not to be required, so it is the examiner’s impression that they do not necessarily implicate that any particular step must be performed. The dependent claims are included in this rejection only inasmuch as they depend from the claims at issue.
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 explained in MPEP 2141 et seq. They 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 1-2, 9, 25, 31-34, 37, 41-43, 60, 87-88, 90, and 95-96 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0051005 A1 by Graupe et al.
Graupe (cited in applicant’s IDS2) discloses the compounds of Formula Ia and Formula Ib and their use in methods of treating or preventing HIV infection. See, e.g., para. 0077-84 and 0091-96. They are administered in a dosing regimen “for a desired period of time or duration, such as at least about one day, at least about one week, at least about one month,” and so forth (para. 0315-16). It is implicit that treatment should continue as long as there is a medical need and that figuring out the optimal time periods, e.g., “first period” and “second period” referred to in claim 1, as well as the time periods referred to in clams 9 and 25, would have been a matter of routine experimentation. For example, the disclosure of “once every couple of days” (para. 0075), would have suggested the time period of “two days” referred to in claim 2.
With respect to the type of dosage form, Graupe discloses (para. 0105 and 0262) the sodium salt of the compound of Formula Ia, as well as solutions (para. 0268), which suggests the subject matter of claims 31-32. Graupe also discloses compositions of “about 5% to 20% water” (para. 0268); using PEG 300 as an excipient (para. 0256), including an example composition having “45% PEG 300” (para. 0397); and a drug concentrations of 200 mg/mL (para. 0429-30), i.e., about 20% active ingredient, which suggests compositions within the meaning of claims 33-34. Graupe further discloses oral administration of tablet dosage forms (para. 0174-82) within the meaning of claim 37. The tablet may be coated (para. 0244), which meets the limitations of claim 43.
With respect to the claimed oral dosage amounts, Graupe discloses that “[t]he amount of active ingredient … may vary depending upon the intended treatment subject and the particular mode of administration,” for example, “a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active material” (para. 0272). The oral dosage amounts recited in claims 41-42 fall within the range disclosed in the reference. In situations like this, where claimed dosage amounts “‘overlap or lie inside ranges disclosed by the prior art,’ a prima facie case of obviousness exists.” See MPEP 2144.05(I) (overlapping, approaching, and similar ranges, amounts, and proportions). Generally, differences in such parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicat-ing the dosage amounts are critical. Where 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 experimen-tation.” See MPEP 2144.05(II)(A) (optimization within prior art conditions or through routine experimentation). The examiner is not aware of any evidence indicating they are critical, so the examiner concludes that the oral dosage amounts referred to in the claims are prima facie obvious over the general teachings of Graupe.
Graupe is silent regarding whether the subject is treatment naïve or heavily pretreated, but it is a reasonable inference that the patient referred to in claim 60 is within the meaning of the “subject” discussed in the reference (para. 0091-102). For example, the reference mentions treatment naïve animals (para. 0399-400), which implicates the existence of corresponding treat-ment-experienced subjects.
With respect to combination therapies, Graupe discloses administration of the compound of Formula Ia “in combination with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents” (para. 0160), which meets the limitations of claim 87. Examples of such combination therapies include “HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase,” and so forth (para. 0178-79), which meets the limitations of claim 88. Further examples include bictegravir (para. 0191), abacavir (para. 0211), tenofovir (para. 0211), and other drugs within the scope of claim 90.
The contingent limitation at the end of claim 1 has not been accorded patentable weight for the reasons previously discussed. See the rejection under § 112(b), above.
Claims 1-23, 25, 29-37, 39-45, 60, 87-88, 90, and 95-96 are rejected under 35 U.S.C. 103 as being unpatentable over Graupe as applied above, and further in view of WO 2020/018459 A1 by Bauer et al.
The disclosure of Graupe is relied upon as set forth above. In addition, with respect to the subcutaneous dosage amounts, Graupe discloses example dosage amounts of “100 mg/mL” and “200 mg/mL” (see Figs. 4-12 and the discussion thereof).
The difference between the prior art and the claims at issue is that Graupe does not specifically disclose the claimed subcutaneous dosage amounts.
Bauer (also cited in applicant’s IDS), however, discloses methods of treating HIV by administering the same compounds of the instant claims (see, e.g., p. 2, ll. 20-26). The compound “is administered subcutaneously at a concentration of about 50 mg/mL to about 500 mg/mL” (p. 4, ll. 22-25), which embraces the narrower concentration limitations of the instant claims. One would have viewed the dosage amounts of Bauer as being alternative embodiments of the same invention disclosed in Graupe. Generally, one would have viewed using the dosage amounts of Bauer when practicing the therapy of Graupe as being a matter of routine experi-mentation. As explained in MPEP 2144.05, the subcutaneous dosage amounts of the instant claims are therefore prima facie obvious.
For example, instant claim 3 requires a subcutaneous dosage amount of “about 309 mg/mL.” This is within the range “of about 50 mg/mL to about 500 mg/mL” taught by Bauer (p. 4, ll. 22-25). Claim 3 also requires an oral dosage amount of “about 500 mg to about 700 mg.” This is within the range of “approximately 1 to 1000 mg of active material” taught by Graupe (para. 0272). The dosage amounts of instant claim 3 are therefore prima facie obvious over the general teachings of the applied references for the reasons discussed in MPEP 2144.05(II) (“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 percentage ranges is the optimum combination of percentages.”). “The dosage or dosing frequency of a compound … can be adjusted over the course of the treatment, based on the judgment of the administering physi-cian.” See Bauer at p. 119, ll. 21-23. This statement is further evidence that one would have arrived at the dosage amounts of the instant claims by optimization within the general teachings of the cited references (see especially Bauer at pp. 120-28). The examiner makes similar conclu-sions about the concentration and dosage limitations of claims 4-8, 10-17, 20-23, 29-30, and 35-36.
Graupe generally discloses that “[p]harmaceutical compositions comprising the compound disclosed herein (e.g. a compound of Formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, may be prepared with conventional carriers (e.g., inactive ingredient or excipient material) which may be selected in accord with ordinary practice” (para. 0237). It is implicit that one of skill in the art would be competent to look into the prior art to determine what is “ordinary practice” in this context, and Bauer provides an answer to this question. Specifically, the subject matter of claims 39-40 is disclosed in Bauer at pp. 102-10. The subject matter of claims 43-45 is disclosed in Bauer at p. 110, ll. 13-34. One would therefore have viewed the dosage forms of claims 39-40 and 43-45 as being prima facie obvious over Graupe in view of Bauer.
The contingent limitations at the end of claims 1 and 29-30 have not been accorded patentable weight for the reasons previously discussed. See the rejection under § 112(b), above.
Claims 1-23, 25, 29-37, 39-45, 60, 87-88, 90, and 95-96 are rejected under 35 U.S.C. 103 as being unpatentable over Graupe and Bauer as applied above, and further in view of Counterman et al., J. Pharmacokinet. Pharmacodyn. 2021;48(6):873-92 and Gu et al., Eur. J. Drug Metab. Pharmacokinet. 2020;45(2):163-72.
The disclosures of Graupe and Bauer are relied upon as set forth above. The difference between the prior art and the claims at issue is that neither of these reference specifically discloses adjusting the dosage amount “if the patient misses or will miss a maintenance dose,” i.e., providing a “bridging dosage” of “about 250 mg to about 650 mg” (see claim 1) or “300 mg” (see claims 29-30). In the rejections above, these contingent limitations have not been accorded patentable weight. This rejection is made in order to provide applicant with an opportunity to address this subject matter in the event that the contingent limitations would, in fact, be given patentable weight.
Counterman is cited as evidence that adjusting dosage amounts in response to a missed or skipped maintenance dosage was known in the prior art. This reference acknowledges that sometimes “patients simply forget[] to take their medication” (p. 874). As a consequence, “[d]oses are missed at random, and thus the drug concentration in the body is random” (p. 874). As a general principle, Counterman suggests that “the effects of nonadherence are best mitigated by taking double doses following missed doses” or, depending on the half-life of the drug, “missed doses should be skipped” (p., 874). Alternatively, “other ways of handling missed doses, including taking an extra half dose following a missed dose” (p. 874) may be appropriate. Counterman provides a mathematical model (pp. 874-90) for calculating how nonadherence to medication affects drug concentrations in the body. The objective is to maximize drug exposure in the therapeutically effective range (see Fig. 6 and the discussion thereof).
Gu is further evidence that determining an “optimum remedial dosing regimen” for a delayed or missed dose was known in the prior art. “Skipping the missed dose and continuing the next dose as normal may lead to a reduced clinical effect or even failure of drug treatment” (p. 163). In order to address this problem, “pharmacometric-based approaches, particularly those based upon population pharmacokinetic/pharmacodynamic (PK/PD) modeling and simula-tion, are thought to be effective in facilitating selection of the optimum remedial regimen under various scenarios of delayed or missed doses, supporting individualized drug therapy” (p. 164). “[C]linical pharmacokinetic data can be translated into computer-based algorithms to optimize pharmacotherapy for patients. Generally, pharmacometric approaches describe the relationship of dose, concentration levels in vivo, and the response to the drug in a quantitative manner. This type of methodology has been applied successfully in drug development and dosage adjust-ments, enabling the prediction of PK/PD profiles under various dosing scenarios for personaliza-tion of drug therapy in different clinical settings, including irregular dosing” (p. 164). The goal of these remedial dosing regimens is to maximize drug concentration within the therapeutic range (see Fig. 2 and the discussion thereof).
In general, it is within the level of ordinary skill in the art to adjust dosage amounts in response to the therapeutic needs of a patient and the clinical situation at hand. To this end, Graupe acknowledges that “[t]he dosage or dosing frequency … may be adjusted over the course of the treatment, based on the judgment of the administering physician” (para. 0318-19). Bauer likewise discloses that “[t]he dosage or dosing frequency … can be adjusted over the course of the treatment, based on the judgment of the administering physician” (p. 119, ll. 21-23). Even applicant’s own specification admits that “a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure” (see the discussion of “effective amount” in applicant’s specification, filed April 18, 2024, at p. 178).
One would therefore have viewed the remedial dosage regimen of the instant claims as being a matter of optimization of dosing amount or timing, by routine experimentation, within the general teachings of the cited references and therefore prima facie obvious. It appears that applicant has simply identified the 300 mg fixed-dose tablets described in Bauer (pp. 185-86) as being a remedial dosage amount (or “bridging dosage”) within the teachings of Counterman and Gu.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possi-ble harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provi-sions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompa-nied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms that may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-23, 25, 29-37, 39-45, 60, 87-88, 90, and 95-96 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-5, 7, 9, 11, 13-15, 20, 25-31, 33-36, 38-39, 41, 47, and 85-92 of copending Application No. 18/785,641 (refer-ence application). Although the claims at issue are not identical, they are not patentably distinct from each other. The claims (submitted on November 12, 2024) of the ‘641 application are drawn to a method of preventing HIV infection comprising administering the same compound and substantially the same dosage amounts as required by the instant claims. Claim 4 of the ‘641 provides for administering a remedial dosage amount “if the patient misses a maintenance dosage.” This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-23, 25, 29-37, 39-45, 60, 87-88, 90, and 95-96 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 7-8, 13-14, 18-36, 38, 41-42, 44, 46-48, 50, 58, 61, 88, and 96-97 of copending Application No. 18/812,842 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other for substantially the same reasons discussed above. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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THEODORE R. HOWELL
Primary Examiner
Art Unit 1628
/THEODORE R. HOWELL/ Primary Examiner, Art Unit 1628
June 1, 2026
1 Manual of Patent Examining Procedure (MPEP), Latest Revision November 2024 [R-01.2024]
2 See the information disclosure statement (IDS) submitted on August 8, 2024.
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