DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/03/2026 has been entered.
Status of the Application
Claims 1-5, 12-14, 16, and 18-22 are pending.
Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on 08/03/2026 are acknowledged. Claims 1 and 16 are amended. Claims under consideration in the instant office action are claims 1-5, 12-14, 16, and 18-22.
Applicants' arguments, filed 08/03/2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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.
Terminal Disclaimer
The terminal disclaimer filed on 08/10/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,654,150 has been reviewed and is accepted. The terminal disclaimer has been recorded.
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, 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).
Claim Interpretation
Claim 1 is a product by process claim, and is limited to the end product as being an oral dosage form comprising a lubricant, a disintegrant, silicon dioxide loaded with GS-9350, and a darunavir granulate comprising about 800 mg free form equivalent of darunavir and particles consisting of darunavir, Hypromellose and any residual water from granulation.
Rejection
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, 12-14, 16, and 18-22 above and further in view of Shen (US 2008/0113021, as disclosed in IDS).
Rejection
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 “As described in Example 1, preparation of the darunavir component as a separate dried darunavir granulate using only hypromellose and water before combining it with the remaining components was critical to achieving a stable tablet (see, e.g., Concept C, page 15, lines 3-5 and Table 6). In contrast, blending all ingredients together produced a formulation that could not be compressed into a tablet (see, e.g., Concept A, Example 1, page 14, lines 6- 9).” The Examiner respectfully disagrees since although Example 1 demonstrates the criticality of the method of granulation of a darunavir composition, such criticality pertains to the method of preparing a darunavir composition compared to other methods of preparation, but is not one arising from the final composition as recited as compared to other darunavir compositions.
Applicant also argues “Applicant maintains that Koziara does not teach any formulation containing both darunavir and silicon dioxide loaded with GS-9350, as required by the claims. Applicant acknowledges that Example 5 of Koziara describes a formulation comprising Formula (Ia) (GS-9350) and colloidal silicon dioxide. However, Koziara neither teaches nor suggests how to formulate darunavir together with silicon dioxide-loaded GS-9350. Although Koziara generally discusses granulation techniques, it provides no guidance regarding how such techniques would be applied to produce an oral dosage form containing both darunavir and silicon dioxide-loaded GS-9350, much less one in which a darunavir granulate is first prepared independently and contains no GS-9350.” The Examiner respectfully disagrees since 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). However, Koziara does not teach silicon dioxide loaded with GS-9350. 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, 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. The teachings of Koziara and Xu thus suggest the claimed composition, and is not required to disclose a particular process of arriving at the claimed composition.
Applicant also argues that “as discussed above, the claims require that the dried darunavir granulate contain only darunavir, hypromellose, and residual granulation water. GS-9350 is therefore not present within the granulate particles themselves. Instead, GS-9350 is added extragranularly before compression. Koziara does not teach or suggest any formulation in which one API in a multi-API composition is first prepared as a dried granulate while the second API is added extragranularly. Rather, Koziara describes a process in which the compound of Formula (I), a suitable solvent, and solid carrier particles are combined to form a first mixture, followed by the optional addition of excipients and another therapeutic agent before any granulation step. Water may then be added to form a wet granulate, which is subsequently dried and processed into a final composition (page 29, line 23 to page 30, line 15).” The Examiner respectfully disagrees since the claimed dosage form recites a granulate comprising darunavir and particles consisting of darunavir, Hypromellose, and residual water, which is suggested by the teachings of Koziara as taught above. The teachings of Koziara and Xu suggest loading an active agent, such as GS-9350, onto silicon dioxide, which then can be combined with darunavir granulate as suggested by Koziara to arrive at the claimed composition.
Conclusion
Claims 1-6, 12-14, 16, and 18-22 are rejected.
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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/ANDREW P LEE/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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