DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of the Application
Claims 1-6, 12-14, 16, and 18-22 are pending.
Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on 09/26/2025 are acknowledged. Claims 1, 6, and 18-19 are amended and new claims 20-22 are added. Claims under consideration in the instant office action are claims 1-6, 12-14, 16, and 18-22.
Applicants' arguments, filed 09/26/2025, have been fully considered but they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained through the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1-2, 4, 6, 12-14, 16, and 18-22 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Koziara (WO 2009/135179, as disclosed in IDS) in view of Xu (Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer, ACS Med. Chem. Lett., 2010, 1, pp. 209-213, as disclosed in IDS).
Koziara teaches compositions comprising a compound of formula (I) and darunavir, in an amount of 5 to 500 mg, which can be used in the treatment of HIV infection (pp. 2, 10, 12, Example 5). Koziara teaches a method of preparing such a composition comprising granulating a mixture of the active ingredient and hydroxypropyl methylcellulose (hypromellose) (pp. 5-7, Examples 1, 10). Koziara teaches that drug mixtures can be dry granulated and compressed (Example 9). As a consequence it would follow that darunavir would be present in the form of a dried granulate. Koziara teaches that active ingredients can be loaded onto colloidal silicon dioxide (pp. 7, 32, Examples 2, 3). Koziara teaches that magnesium stearate can be added dried granulate and blended for a final powder blend that is compressed (Example 10), which can be present in an amount of 0.5% to 1.5% (pg. 8, lines 7-10). Koziara teaches that tablets can be film coated (pg. 35). Koziara teaches the size of drug particles in the range of about 10 to about 120 microns (Example 7).
Koziara does not teach silicon dioxide loaded with GS-9350.
Xu is drawn towards Cobicistat (GS-9350) as a pharmacoenhancer of other anti-HIV drugs (see abstract). Xu teaches that GS-9350 shows reduced liability for drug interactions and may have potential improvements in tolerability, has high aqueous solubility, and can be readily coformulated with other agents (see abstract).
It would have been obvious to one of ordinary skill in the art to load GS-9350 onto silicon dioxide, as suggested by Xu, and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since Xu teaches that GS-9350 can be combined with other anti-HIV agents such as the ones disclosed by Koziara for enhanced pharmacokinetic effects (right column, first paragraph, pg. 212). Given that drugs can be loaded onto colloidal silicon dioxide as taught by Koziara ((pp. 7, 32, Examples 2, 3), one of ordinary skill in the art would have been motivated to load GS-9350 onto silicon dioxide, with a reasonable expectation of success absent evidence of criticality of the particular steps.
Regarding the limitation wherein the oral dosage form includes free form equivalent of darunavir of about 400 mg to 800 mg or 50% to 60%, and 17% to 20% of silicon dioxide loaded with GS-9350, Koziara teaches compositions comprising a compound of formula (I) and darunavir, in an amount of 5 to 500 mg, which can be used in the treatment of HIV infection (pp. 2, 10, 12, Example 5). Even though the range for the component amounts as taught by Koziara is not the same as the claimed ranges, Koziara does teach an overlapping range for the component amounts, and it has been held that in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Furthermore, it would have been obvious to optimize the component amounts and arrive at the overlapping range in order to increase the therapeutic activity of the formulation depending on the patient, with a reasonable expectation of success absent evidence of criticality for the claimed values.
With regards to the limitation claimed in instant claims 20-21, which recites wherein the weight:weight ratio of darunavir:GS-9350 is in the range of from about 10: 1 to about 4:5, or 5:1, Koziara and Xu do not specifically teach the exact ratios claimed in instant claims 20-22. However, it would be within the skill of an ordinary artisan to be able to modify the ratios in order to obtain the desired enhanced pharmacokinetic effects. 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).
With regards to the limitation claimed in instant claims 18-19, which claims an average particle size between 100 and 500 microns or about 300 microns, Koziara teaches the size of drug particles in the range of about 10 to about 120 microns (Example 7). However, it would be within the skill of an ordinary artisan to be able to modify the particle size in order to obtain the desired stability and drug release properties. 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).
Claims 3 and 5 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Koziara (WO 2009/135179, as disclosed in IDS) and Xu (Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer, ACS Med. Chem. Lett., 2010, 1, pp. 209-213, as disclosed in IDS) as applied to claims 1-2, 4, 6, 12-14, 16, and 18-22 above and further in view of Shen (US 2008/0113021, as disclosed in IDS).
The teachings of Koziara and Xu are presented above.
Koziara and Xu do not teach a composition further comprising hypromellose 2910 and crospovidone.
Shen is drawn towards ibuprofen formulations with reduced throat burn characteristics (paragraph 0001). Shen teaches such formulations comprising hypromellose 2910 and crospovidone (Examples 1 and 2).
It would have been obvious to one of ordinary skill in the art to formulate a composition comprising hypromellose 2910 and crospovidone, as suggested by Shen, and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since such well known excipients improve the oral administration of the formulation as taught by Shen, with a reasonable expectation of success absent evidence of criticality of the particular formulation.
Response to Arguments
Applicant argues that “None of the cited references teaches or suggest the making a separate preparation of the dried darunavir granulate before combining it with other components as claimed. Moreover, none of the cited references provide any examples of formulating darunavir and GS-9350, and thus none of the cited references even acknowledges that achieving a stable tablet containing both darunavir and GS-9350 is a problem. It is only the present application that describes the difficulties with producing a stable oral dosage form containing darunavir and GS-9350, and it is only the present application that provides a solution to this problem.” The Examiner respectfully disagrees since the prior art as outlined above reads on the limitation of the composition as recited, which is not drawn towards a method of preparation.
Applicant also argues that “Koziara does not describe any method for how to combine darunavir with a compound of Formula (I), let alone describe that for successful formulation of the two APis into an oral dosage form that the darunavir must be present in a pre-formulated dried darunavir granulate that consists of darunavir, hypromellose and residual water from granulation. The dried darunavir granulate is a distinct component of the oral dosage form. Koziara does not teach any oral dosage form containing this distinct component.” The Examiner respectfully disagrees since Koziara teaches darunavir as an API, and Koziara teaches a method of preparing such a composition comprising granulating a mixture of the active ingredient and hydroxypropyl methylcellulose (hypromellose) (pp. 5-7, Examples 1, 10). Koziara teaches that drug mixtures can be dry granulated and compressed (Example 9). It would thus be obvious to one of ordinary skill in the art to form a granulate of darunavir and Hpromellose for an oral dosage form.
Applicant also argues that “Koziara does not teach or suggest any oral dosage comprising 2 therapeutic agents, where one of the therapeutic agents is present in a distinct pre-formed dried granulate, let alone where that therapeutic agent is darunavir.” The Examiner respectfully disagrees since Koziara teaches compositions comprising a compound of formula (I) and darunavir, in an amount of 5 to 500 mg, which can be used in the treatment of HIV infection (pp. 2, 10, 12, Example 5). Koziara teaches a method of preparing such a composition comprising granulating a mixture of the active ingredient and hydroxypropyl methylcellulose (hypromellose) (pp. 5-7, Examples 1, 10). Koziara teaches that drug mixtures can be dry granulated and compressed (Example 9).
Applicant also argues that “Not only do the claimed dried darunavir granulates provide for incorporation of high drug loads in single unit dosage forms, but the claimed dried darunavir granulates can result in about a 25% reduction in the size and weight of lower-dosage darunavir dosage forms, e.g., equivalent to 400 and 600 mg of darunavir. (Id. at page 5, lines 1-4). Even additional active ingredients can be incorporated into the dosage forms without increasing pill burden. (Id. at page 5, lines 6-10). The surprising manufacturing advantages that the claimed granulate compositions are able to provide could not have been predicted based on the cited publications.” The Examiner respectfully disagrees since the prior art renders obvious a formulation comprising darunavir in the form of a dry granulate as discussed above, and Applicant has not provided a comparative of compositions of the prior art and the claimed invention that demonstrates unexpected results.
Applicant also argues that “Koziara does not teach or suggest any amount of darunavir in a formulation with Formula (Ia) (GS-9350).” The Examiner respectfully disagrees since Koziara teaches compositions comprising a compound of formula (I) and darunavir, in an amount of 5 to 500 mg, which can be used in the treatment of HIV infection (pp. 2, 10, 12, Example 5).
Applicant also argues that “It does not teach or suggest any oral dosage form the contains a dried darunavir granulate that is distinct from the other components within the oral dosage form.” The Examiner respectfully disagrees since the teachings of Koziara disclose darunavir as an API (see abstract), which can be dry granulated as discussed above. Additionally, the claimed invention does not recite a dried granulate consisting of darunavir given the recitations of the claimed invention, wherein “the dried darunavir granulate comprises”.
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 possible 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 provisions 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 accompanied 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 which 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 1-6, 12-14, 16, and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,654,150.
Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims both recite similar oral dosage forms of darunavir. U.S. Patent No. 11,654,150 is drawn towards a method of preparing a composition comprising darunavir, microcrystalline cellulose, Hypromellose, and silicon dioxide loaded with GS-9350.
U.S. Patent No. 11,654,150 does not explicitly recite a composition comprising darunavir.
It would have been obvious to one of ordinary skill in the art to formulate a composition comprising darunavir, as suggested by U.S. Patent No. 11,654,150, and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since U.S. Patent No. 11,654,150 does disclose a method of preparing such a composition, with a reasonable expectation of success absent evidence of criticality of the particular steps.
Response to Arguments
Applicant argues that the “The claims currently pending in the present application are all directed to an oral dosage form comprising darunavir. Because the office has asserted that such subject matter is independent and distinct from a method of preparing a composition comprising darunavir, there can be no issue of double patenting. The present claims are consonant with the restriction requirement issued on July 1, 2021 in the parent '888 Application and are drawn to a non-elected invention pursuant to that restriction requirement. Moreover, the Office has asserted that a method of preparing a composition comprising darunavir is independent and distinct in the present application.” The Examiner respectfully disagrees since although the inventions as recited in the instant application are independent and distinct from one another does not result in a finding regarding other inventions recited in other applications. The method recited in the ‘888 Application is not the same as the method claimed in the instant application. Thus, it would not be dispositive regarding a finding of obviousness based on the ‘888 Application.
Conclusion
Claims 1-6, 12-14, 16, and 18-22 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREW P LEE whose telephone number is (571)270-1016. The examiner can normally be reached Monday-Friday 9am-5pm.
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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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/ANDREW P LEE/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691