DETAILED ACTION
This office action is in response to applicant’s filing dated March 23, 2026.
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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 23, 2026 has been entered.
Status of Claims
Claims 1-5, 8-10, 13, 14, 17, 18, 21, 28, 33, 35-39, 42-44, and 46-51 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed March 23, 2026. Acknowledgement is made of Applicant's amendment of claims 1, 2, and 44; cancelation of claims 12, 19, and 20; and addition of new claims 46-51. Claims 6, 7, 11, 15, 16, 22-27, 29-32, 34, 40, 41, and 45 were previously canceled.
Priority
The present application is a CON of PCT/US2023/065417 filed on April 6, 2023, which claims benefit of Provisional Application Nos. 63/329,257; 63/380,908; and 63/479,683 filed on April 8, 2022; October 25, 2022; and January 12, 2023.
Modified Objections and/or Rejections
Claim Rejections - 35 USC § 103
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 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.
Claims 1, 3, 4, 8-10, 13, 14, 21, 28, 42-44, and 46-51 are rejected under 35 U.S.C. 103 as being unpatentable over Burrows et al (WO 2020/205486 A1, cited in the IDS filed July 20, 2023) in view of Reagan-Shaw et al (FASEB J, 2007; 22:659-661, cited in the IDS filed July 20, 2023) and Dunn et al (Int J Radiation Oncol Biol Phys, 2020; 106(3):564-570).
Regarding claim 1, Burrows teaches a method of treating a squamous cell carcinoma (SCC) in a subject, comprising administering a therapeutically effective amount of a farnesyltransferase inhibitor (FTI) (claim 1), wherein the SCC is head and neck SCC (HNSCC) (claims 13-17), wherein the FTI is tipifarnib (claims 32 and 33); wherein the tipifarnib is administered before, during, or after the administration of a second active agent (claims 46 and 47), wherein said second active agent is an PI3K-α inhibitor (claim 48 and 55), wherein said PI3K-α inhibitor is BYL719 (claim 56). Burrows teaches in some embodiments, the HNSCC is metastatic HNSCC; and in some embodiments, the HNSCC is relapsed HNSCC [0089]. Relapsed reads on recurrent.
BYL719 is equivalent to alpelisib as evidenced by the instant specification (see page 4, 1st paragraph). Burrow teaches the term “administer,” “administering,” or “administration” refers to the act of delivering or causing to be delivered, a compound or a pharmaceutical composition to the body of a subject by a method described herein or otherwise known in the art; administering a compound or a pharmaceutical composition includes prescribing a compound or a pharmaceutical composition to be delivered into the body of a patient; exemplary forms of administration include oral dosage forms, such as tablets, capsules, syrups, suspensions [0052].
Burrow further teaches mice were inoculated subcutaneously on the flank with PDX HNSCC having high H-Ras expression; after tumor development, mice were administered a combination of tipifarnib and a second active agent; and the second agent was BYL719 (50mg/kg PO QD).
Thus, Burrows teaches a method of treating recurrent/metastatic HNSCC comprising administering tipifarnib and alpelisib and teaches administering includes oral administration.
Regarding the amount of tipifarnib of instant claims 1 and 46-51, Burrows teaches tipifarnib is administered at a dose of 100-1200 mg twice a day (claim 38) which is equivalent to 200mg-2400mg per day. Burrows does not explicitly teach the amount of alpelisib of instant claims 1 and 46-51.
However, the Examiner notes that a 50 mg/kg dose in a mouse is equivalent to approximately a 4 mg/kg human equivalent dose (HED) as taught by Reagan-Shaw. Reagan-Shaw teaches the formula for dose translation based on body surface area (BSA) is (Figure 1):
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182
472
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Reagan-Shaw teaches the Km factor for a rat is 3 and for a human adult, is 37 (Table 2):
50 mg/kg (rat dose) * 3 (rat Km) / 37 (Human Km) = 4 mg/kg (HED)
A dose of 4 mg/kg in an average adult human weighing about 60 kg is equivalent to a 240 mg dose which anticipates the instantly claimed range (10 to 400 mg).
Moreover, Dunn teaches a method of treating head and neck squamous cell carcinoma comprising administering BYL719 (title); BYL719 was given orally in 3 dose levels (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose escalation design (page 565, methods and materials); and the recommended phase 2 dose of BYL719 is 250 m/d (page 565, Conclusions). Thus, Dunn establishes that 250 mg/d or 300 mg/d were amounts of BYL719 suitable in combination therapies for treating HNSCC.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to utilize the human equivalent dose of the mice doses tested and the amounts of BYL719 taught to be useful in combination therapies for treating HNSCC as the starting point for optimizing the amount of alpelisib for use in a method of treating recurrent/metastatic HNSCC in a patient being treated with tipifarnib and alpelisib.
Regarding the limitation “wherein the HNSCC is a PIK3CA-dependent HNSCC,” Burrows teaches effect of tipifarnib and second therapies in HNSCC with mutant H-Ras expression and with or without co-Mutations in PIK3CA [00399]; mice were inoculated subcutaneously on the flank with PDX HNSCC models having high H-Ras expression levels and having wild type PIK3CA expression levels HN3067 or having high H-Ras expression levels and having mutated PIK3CA expression levels HN2593 and HN3690, wherein the mutation is or comprises a modification in a codon of the mutant PIK3CA gene; after tumor development, mice were administered either vehicle, tipifarnib (at a reduced dosing of 60mg/kg PO BID), a second active agent, or a combination of tipifarnib and a second active agent; the second agent was PBK-a inhibitor BYL719; when PI3K-a inhibitor BYL719 was combined with tipifarnib, it resulted in further inhibition of tumor growth in each of the models (FIGS. 16A-16D), relative to tipifarnib
monotherapy or relative to PI3K-a inhibitor BYL719 monotherapy in said models; the
combination therapy induced tumor regression in one of the high H-Ras expression/wild type
PIK3CA expression models, relative to vehicle; as such, tipifarnib not only directly inhibited tumor growth in the high H-Ras expression/wild type PIK3CA expression models and in the high H-Ras expression/mutated PIK3CA expression models, but also increased the sensitivity of the tumor to PI3K-a inhibitor BYL719 treatments in each of these models [00400].
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to utilize the method of treating HNSCC taught by Burrows to treat PIK3CA-dependent HNSCC with a reasonable expectation of success, since the art teaches combination of tipifarnib and alpelisib induced tumor regression in both wild-type and high H-Ras expression/mutated PIK3CA expression models.
Regarding claims 3, 4, 42, and 43, the wherein limitations of these claims, are considered to simply express the intended result of a process step positively recited, which is not given patentable weight (See MPEP 2111.04: [T]he court noted (quoting Minton v. Nat'lAss'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQgd 1614, 1690 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.'" Hoffer v. Microsoft Corp., 405 F.3d 1396, 1399, 74 USPQgd 1481, 1483 (Fed. Cir. 2005).).
Regarding claim 21, Burrows teaches the FTI can be administered before the administration of a second active agent; the FTI can be administered concurrently with a second active agent; and the FTI can be administered after the administration of a second active agent [0342].
Taken together, all this would result in the practice of the method of claims 1, 3, 4, 21, 42, and 43 with a reasonable expectation of success.
Regarding claims 8, 13, and 14, Burrows teaches in some embodiments the PI3K inhibitor is BYL719 and the combined uses of BYL719 and an FTI in selectively treating SCC in subjects having H-Ras overexpression [00360]. Moreover, Burrows combination treatment of tipifarnib and BYL719 inhibited tumor growth in HNSCC PDX Models HN3067 and HN3411 having high H-Ras expression levels and wild type PIK3CA expression, and in PDX HNSCC models HN2593 and HN3690 having high H-Ras expression levels and having mutated PIK3CA expression [0042]. Burrows teaches all models in Table 1 express wild type H-Ras and include HN3067, HN3411, HN2593, and HN3690. It would have been prima facie obvious to one of ordinary skill in the art to utilize the method of treating HNSCC comprising administering tipifarnib and alpelisib to treat HNSCC with an overexpression of wild-type HRas protein (instant claim 8) wherein the HNSCC has a PIK3CA alteration or dysregulation with a reasonable expectation of success, since Burrows teaches combination treatment of tipifarnib and BYL719 is useful treating SCC having H-Ras overexpression and inhibited tumor growth in HNSCC models having high H-Ras expression and mutated PIK3CA expression.
Taken together, all this would result in the practice of the method of claims 8 and 12-14 with a reasonable expectation of success.
Regarding claims 9 and 10, Burrows teaches in some embodiments the SCC also has an H-Ras mutation; in some embodiments, the H-Ras mutation includes an amino acid substitution at a codon selected from a group consisting of G12, G13, Q61, Q22, K17, A146, and any combination thereof [0006]; in some embodiments, the mutant HRAS gene encodes a mutant H-Ras protein, wherein the HRAS gene mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from a group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof, in the corresponding mutant H-Ras protein [0007]. Moreover, Burrows teaches in some embodiments the combined use of BYL719 and tipifarnib in selectively treating SCC in subjects carrying an H-Ras gene mutation [00360]; in some embodiments the SCC is HNSCC [00361]. It would have been prima facie obvious to one of ordinary skill in the art to utilize the method of treating HNSCC comprising administering tipifarnib and alpelisib to treat HNSCC wherein the HNSCC has an HRas protein mutation with a reasonable expectation of success, since Burrows teaches combination treatment of tipifarnib and BYL719 is useful treating SCC having H-Ras protein mutation.
Taken together, all this would result in the practice of the method of claims 9 and 10 with a reasonable expectation of success.
Regarding claim 28, Burrows teaches tipifarnib is administered at a dose of 100-1200 mg twice a day (claim 38). MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Taken together, all this would result in the practice of the method of claim 28 with a reasonable expectation of success.
Regarding claim 44, Burrows does not explicitly teach a pharmaceutical kit comprising pharmaceutical composition comprising tipifarnib and a pharmaceutical acceptable carrier and a pharmaceutical composition comprising alpelisib and a pharmaceutically acceptable carrier. The amount of alpelisib has been addressed above. As set forth above, Burrows teaches the FTI can be administered before the administration of a second active agent and the FTI can be administered after the administration of a second active agent [0342]. Thus, Burrows suggests administering the alpelisib and tipifarnib in separate formulations. Moreover, Burrows teaches for oral administration, a pharmaceutically acceptable nontoxic composition is formed by the incorporation of any of the normally employed excipients [00276]. Moreover, Burrows teaches compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits; suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs and strip packs [00282]. Before the effective filing date of the invention, It would have been prima facie obvious to one of ordinary skill in the art to produce a pharmaceutical kit comprising pharmaceutical composition comprising tipifarnib and a pharmaceutical acceptable carrier and a pharmaceutical composition comprising alpelisib and a pharmaceutically acceptable carrier in view of the teachings of Burrows.
Taken together, all this would result in the practice of the method of claim 44 with a reasonable expectation of success.
Claims 2, 5, 17, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Burrows et al (WO 2020/205486 A1, cited in the IDS filed July 20, 2023) in view of Reagan-Shaw et al (FASEB J, 2007; 22:659-661, cited in the IDS filed July 20, 2023) and Dunn et al (Int J Radiation Oncol Biol Phys, 2020; 106(3):564-570) as applied to claims 1, 3, 4, 8-10, 13, 14, 21, 28, 42-44, and 46-51 above, and further in view of Tsuchihashi et al (Oncology Reports, 2020; 44:863-872, cited in a previous Office Action).
As set forth above, Burrows, Reagan-Shaw, and Dunn teach a method of treating HNSCC comprising administering tipifarnib and alpelisib wherein the recurrent/metastatic HNSCC is refractory. The cited references do not teach the patient is cetuximab resistant.
However, Tsuchihashi teaches over the last 30 years, systemic therapeutic (drug therapy) guidelines for patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) have not changed; in 2008, the Extreme trial (2) found that the addition of cetuximab (trade name Erbitux™ , a molecular targeted agent against epidermal growth factor receptor (EGFR), to the standard platinum and 5-fluorouracil (5-FU) regimen improved median overall survival (OS) and progression-free survival (PFS) in HNSCC; National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines have also suggested that systemic therapy, including cetuximab, should be listed as the recommended category 2B for its effectiveness in treating very advanced HNSCC; however, some OSCC tumors acquired resistance with long-term cetuximab administration (page 863, right, 1st paragraph). Tsuchihashi teaches although cetuximab is reported to have significant therapeutic efficacy against HNSCC, the PIK3CA gene is a candidate gene involved in the acquired resistance to long-term cetuximab treatment due to point mutations within the gene (page 863, right, 2nd paragraph); PIK3CA point mutation may promote cetuximab resistance in HNSCC; copy number amplifications and gene point mutations of PIK3CA have also been reported in OSCC and observed in advanced stages of OSCC (page 864, left, 1st paragraph). Tsuchihashi teaches the NCCN Clinical Practice Guideline has suggested that systemic therapy (drug therapy), including cetuximab is the standard treatment for very advanced HNSCC; however, in some cases resistance to long-term administration of cetuximab develops, and new lesions can appear (page 869, right, 1st paragraph). Tsuchihashi teaches in the preclinical study of HNSCC, alpelisib was shown to overcome cetuximab resistance in HNSCC; alpelisib treatment reduced Akt activation and suppressed tumor growth in HNSCC, in vitro and in vivo (page 869, right, last bridge paragraph and 870).
As such, since Burrows and Reagan-Shaw teach a method of treating HNSCC comprising administering tipifarnib and alpelisib wherein the HNSCC is refractory, and since Tsuchihashi teaches that alpelisib was shown to overcome cetuximab resistance in HNSCC; before the effective filing date of the invention, it would have been prima facie obvious for a person of ordinary skill in the art modify the method of treating HNSCC comprising administering tipifarnib and alpelisib wherein the HNSCC is refractory to treat HNSCC that is cetuximab-resistant with an expectation of success, since the prior art establishes that the combination of tipifarnib and alpelisib is useful for treating refractory HNSCC and alpelisib is was shown to overcome cetuximab resistance in HNSCC.
Regarding claim 5, the wherein limitations of these claims, are considered to simply express the intended result of a process step positively recited, which is not given patentable weight (See MPEP 2111.04: [T]he court noted (quoting Minton v. Nat'lAss'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQgd 1614, 1690 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.'" Hoffer v. Microsoft Corp., 405 F.3d 1396, 1399, 74 USPQgd 1481, 1483 (Fed. Cir. 2005).).
Taken together, all this would result in the practice of the method of claims 2 and 5 with a reasonable expectation of success.
Regarding claims 17 and 18, as set forth above, Burrows and Reagan-Shaw suggest a method of treating HNSCC comprising administering tipifarnib and alpelisib wherein HNSCC has an overexpression of wild-type HRas protein and wherein the HNSCC has a PIK3CA gene alteration or dysregulation. Burrows and Reagan-Shaw do not explicitly teach treating a PIK3CA alteration wherein the alteration is a PIK3CA gene amplification or a PIK3CA copy gain. However, PIK3CA gene is a candidate gene involved in the acquired resistance to long-term cetuximab treatment due to point mutations within the gene (page 863, right, 2nd paragraph); PIK3CA point mutation may promote cetuximab resistance in HNSCC; copy number amplifications and gene point mutations of PIK3CA have also been reported in OSCC and observed in advanced stages of OSCC. It would have been prima facie obvious for a person of ordinary skill in the art modify the method of treating HNSCC comprising administering tipifarnib and alpelisib wherein the HNSCC is refractory taught by Burrows and Reagan-Shaw to treat HNSCC that is cetuximab-resistant wherein the HNSCC has a PIK3CA dysregulation wherein the dysregulation is a PIK3CA gene amplification or copy gain with an expectation of success, since the prior art establishes that the combination of tipifarnib and alpelisib is useful for treating refractory HNSCC; alpelisib is was shown to overcome cetuximab resistance in HNSCC; and copy number amplifications and gene point mutations of PIK3CA have also been reported in OSCC and observed in advanced stages of OSCC. OSCC is a species of HNSCC and thus reads on HNSCC.
Taken together, all this would result in the practice of the method of claims 17 and 18 with a reasonable expectation of success.
Claims 33 and 35-39 are rejected under 35 U.S.C. 103 as being unpatentable over Burrows et al (WO 2020/205486 A1, cited in the IDS filed July 20, 2023) in view of Reagan-Shaw et al (FASEB J, 2007; 22:659-661, cited in the IDS filed July 20, 2023) and Dunn et al (Int J Radiation Oncol Biol Phys, 2020; 106(3):564-570) as applied to claims 1, 3, 4, 8-10, 13, 14, 21, 28, 42-44, and 46-51 above, and further in view of Razak et al (J Clin Oncol, 2014; 32(15suppl):6044, cited in a previous Office Action).
Regarding claim 33, as set forth above, Burrows, Reagan-Shaw, and Dunn teach a method of treating HNSCC comprising administering tipifarnib and alpelisib wherein the HNSCC is refractory. As set forth above, Burrows teaches treating HNSCC comprising administering tipifarnib and alpelisib wherein alpelisib is administered in a human equivalent dose of 240 mg dose. Moreover, Razak teaches a Phase Ib/II study of a combination comprising BYL719 administered to patients with recurrent/metastatic squamous cell cancer of the head and neck (Title and background); wherein BYL719 was administered QD in 28-day cycles as whole tablets (Methods); patients treated with BYL719 300 mg QD or 400 mg QD (Results); and combination comprising BYL719 was tolerated and demonstrated encouraging antitumor activity (Conclusions). Thus, Razak teaches administering alpelisib orally. QD reads on once per day.
Regarding claims 35-39, Burrows teaches tipifarnib is administered on days 1-7 of a 28-day treatment cycle (claim 42); tipifarnib is administered on days 1-7 and 15-21 of a 28-day treatment cycle (claim 40); tipifarnib is administered on days 1-21 of a 28-day treatment cycle (claim 41); and tipifarnib is administered twice a day (claim 37). Razak teaches BYL719 was administered QD in 28-day cycles.
It would have been prima facie obvious to one of ordinary skill in the art to utilize the amounts and treatment regimens of alpelisib taught by Burrows and Razak and treatment regimens of tipifarnib taught by Burrows as a starting point to optimize the amount and dosing regimen of alpelisib used in combination with tipifarnib to treat HNSCC since Burrows and Razak teach alpelisib and tipifarnib are useful for treating HNSCC and because dosage and treatment regimen are result-effective variables, i.e. a variable that achieves a recognized result. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Taken together, all this would result in the practice of the method of claims 33 and 35-39 with a reasonable expectation of success.
Response to Arguments
Applicant argues:
As explained in the Applicant's prior Responses, nothing in the cited references would have motivated one of ordinary skill in the art to select the BSA model of Reagan-Shaw and the Burrows data, and then combine them as suggested by the Office with a reasonable expectation of success in identifying a suitable therapeutic dose at least because: (1) the BSA model is inapplicable to the claimed situation; (2) the Burrows data is not suitable as an input for the Reagan-Shaw BSA model; (3) different allometric scaling methods yield varying and unpredictable results; (4) more sophisticated models were preferred in the field at the time of the present application, but required intensive pharmacokinetic data not described in Burrows; and (5) Reagan-Shaw and others taught away from use of the BSA model by detailing its limitations and advocating evolved approaches.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As set forth previously on the record, Burrows teaches a method of treating HNSCC comprising orally administering tipifarnib, in amounts that render the instantly claimed amounts obvious, and alpelisib. The teachings of Reagan-Shaw were relied upon to establish that methods of converting animal doses to human equivalent doses were known in the art before the effective filing date of the invention and a skilled artisan would have a reasonable expectation of success by utilizing the method of converting animal doses to human equivalent doses taught by Regan-Shaw, one would arrive at doses of alpelisib to utilize as a starting point for optimizing the amount of alpelisib utilized in combination with tipifarnib for use in a method of treating HNSCC.
Regarding the arguments that the Regan-Shaw model is not suitable, the examiner cites US FDA (USFDA. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Adult Healthy Volunteer. Rockville, MD: US Food and Drug Administration; 2005) and Saadh et al (Sys Rev Pharm 2020;11(8):98-101). US FDA, cited for evidentiary purposes, teaches the same Formula for dose translation based on BSA and the same Km values for mouse conversion (see page 660). Saadh, cited for evidentiary purposes, cites the US FDA guidelines and provides the same conversion equation and Km values. Thus, these references clearly establish that the method of converting animal doses to human equivalent doses was well known in the art and commonly utilized. Moreover, as set forth above, Dunn teaches a method of treating head and neck squamous cell carcinoma comprising administering BYL719 (title); BYL719 was given orally in 3 dose levels (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose escalation design (page 565, methods and materials); and the recommended phase 2 dose of BYL719 is 250 m/d (page 565, Conclusions). Thus, Dunn establishes that 200 mg/d, 250 mg/d, or 300 mg/d were amounts of BYL719 suitable in combination therapies for treating HNSCC. As set forth above, it would have been obvious to one of ordinary skill in the art to utilize the human equivalent dose of the mice doses tested and the amounts of BYL719 taught to be useful in combination therapies for treating HNSCC as the starting point for optimizing the amount of alpelisib for use in a method of treating HNSCC in a patient being treated with tipifarnib and alpelisib.
Applicant argues:
The alleged HED mg dosage of alpelisib calculated by the Office using the BSA model (240 mg) does not suggest the claimed alpelisib doses of 250 or 300 mg per day. Moreover, nothing in the cited references provides a reasonable expectation that the alleged HED mg dosage of alpelisib would be therapeutically effective for treatment of recurrent/metastatic PIK3CA-dependent HNSCC in a patient, let alone any HNSCC.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As set forth previously, US FDA, cited for evidentiary purposes, teaches the same Formula for dose translation based on BSA and the same Km values for mouse conversion (see page 660). Saadh, cited for evidentiary purposes, cites the US FDA guidelines and provides the same conversion equation and Km values. Thus, these references clearly establish that the method of converting animal doses to human equivalent doses was well known in the art and commonly utilized. Moreover, as set forth above, Dunn teaches a method of treating head and neck squamous cell carcinoma comprising administering BYL719 (title); BYL719 was given orally in 3 dose levels (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose escalation design (page 565, methods and materials); and the recommended phase 2 dose of BYL719 is 250 m/d (page 565, Conclusions). Thus, Dunn establishes that 200 mg/d, 250 mg/d, or 300 mg/d were amounts of BYL719 suitable in combination therapies for treating HNSCC. As set forth above, it would have been obvious to one of ordinary skill in the art to utilize the human equivalent dose of the mice doses tested and the amounts of BYL719 taught to be useful in combination therapies for treating HNSCC as the starting point for optimizing the amount of alpelisib for use in a method of treating HNSCC in a patient being treated with tipifarnib and alpelisib.
Applicant argues:
Dunn does not cure the deficiencies of Burrows and Reagan-Shaw. As Applicant
explained in its Response of September 3, 2025, a skilled artisan would not expect the effects of BYL719 on the toxicities of cetuximab plus radiation or of tipifarnib to be the same in view of the structural and functional differences between those two agents and the inclusion of radiation therapy in one but not the other approach. Furthermore, the skilled artisan would recognize that Dunn is focused on treatment of stage III-IVB head and neck squamous cell carcinoma, which is a locally advanced cancer, and says nothing about treatment of recurrent/metastatic PIK3CA- dependent HNSCC. Accordingly, the skilled artisan would have had no reason to believe that doses of alpelisib used in combination with cetuximab and radiation for treatment of a locally advanced cancer in Dunn would be a good "starting point" for use in combination with an entirely different agent (tipifarnib) for treatment of recurrent/metastatic PIK3CA-dependent HNSCC.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As set forth previously on the record, Burrows teaches a method of treating HNSCC comprising orally administering tipifarnib, in amounts that render the instantly claimed amounts obvious, and alpelisib. The Examiner acknowledges that Dunn does not teach the combination of tipifarnib and alpelisib. However, as set forth above, Dunn teaches a method of treating head and neck squamous cell carcinoma comprising administering BYL719 (title); BYL719 was given orally in 3 dose levels (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose escalation design (page 565, methods and materials); and the recommended phase 2 dose of BYL719 is 250 m/d (page 565, Conclusions). Thus, Dunn explicitly teaches that 200 mg/d, 250 mg/d, or 300 mg/d are amounts of BYL719 suitable in combination therapy for treating HNSCC. The skilled artisan would have been motivated to utilize amounts known to be useful when combined with another agent for treating HNSCC together with the calculated human equivalent dose as a starting point for optimizing the dose of alpelisib/BYL719 used in combination with tipifarnib for the treatment of HNSCC. The motivation would have been the teachings of Burrows that the combined administration of tipifarnib and alpelisib inhibited tumor growth in a HNSCC mouse model ([0041 and Figs 15A-15D) and that 200 mg/d, 250 mg/d, or 300 mg/d are amounts of BYL719 suitable for administration to a human in combination with a second anticancer agent in subjects suffering from HNSCC.
Applicant argues:
The combination of Burrows, Reagan-Shaw, and Dunn does not teach or suggest each and every limitation of the claims, and one of ordinary skill in the art would not have been motivated to combine the teachings of these references in the manner suggested by the Office, with any reasonable expectation of success. Tsuchihashi does not cure these deficiencies. Accordingly, Applicant submits that claims 2, 5, 17, and 18 are patentable over Burrows in combination with Reagan-Shaw, Dunn, and Tsuchihashi.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive Applicant has not independently argued the merits of this rejection. Arguments regarding Burrows, Reagan-Shaw, and Dunn have been addressed above. Therefore, the rejection is maintained for the reasons set forth on the record and for those set forth in the response to the arguments above.
Applicant argues:
The combination of Burrows, Reagan-Shaw and Dunn does not teach or suggest each and every limitation of the claims, and one of ordinary skill in the art would not have been motivated to combine those references as proposed by the Office, with any reasonable expectation of success. Razak does not cure the deficiencies of Burrows, Reagan-Shaw, and Dunn, as it too fails to disclose use of particular claimed doses of alpelisib in combination with tipifarnib. The Office relies on Razak only for the concepts of oral dosing and once daily dosing of alpelisib. Accordingly, Applicant submits that claims 33 and 35-39 are patentable over Burrows in combination with Reagan-Shaw, Dunn, and Razak, and therefore respectfully requests withdrawal of the instant rejection. Accordingly, Applicant submits that claims 33 and 35-39 are patentable over Burrows in combination with Reagan-Shaw, Dunn, and Razak.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive Applicant has not independently argued the merits of this rejection. Arguments regarding Burrows, Reagan-Shaw, and Dunn have been addressed above. Therefore, the rejection is maintained for the reasons set forth on the record and for those set forth in the response to the arguments above.
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 1-5, 8-10, 13, 14, 17, 18, 21, 28, 33, 35-39, 42-44, and 46-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-50 of U.S. Patent No. 11,672,774 in view of Razak et al (J Clin Oncol, 2014; 32(15suppl):6044, cited in a previous Office Action).
The instant claims are directed to a method of treating head and neck squamous cell carcinoma (HNSCC) in a patient comprising administering to the patient (a) tipifarnib and (b) 10-400 mg of alpelisib.
The previously allowed claims are directed to a method of treating wild-type H-Ras-overexpressing head and neck squamous cell carcinoma (HNSCC) in a subject, comprising administering a therapeutically effective amount of tipifarnib and a therapeutically effective amount of PI3K-α inhibitor BYL719 to the subject having wild-type H-Ras-overexpressing HNSCC, wherein the HNSCC is metastatic (claim 5) or relapsed (claim 6); wherein the HNSCC has a PIK3CA gene mutation (claim 15). The previously allowed claims are directed to a method of treating a species of HNSCC also encompassed by the instant claims (see claim 8) with the same compounds. The previously allowed claims are further directed to species of HNSCC which would anticipate the genus of HNSCC of the instant claims. The amounts and dosing regimen of tipifarnib are the same or very similar. The previously allowed claims do not disclose the claimed amount of alpelisib or the dosing regimen.
However, Razak teaches a Phase Ib/II study of a combination comprising BYL719 administered to patients with recurrent/metastatic squamous cell cancer of the head and neck (Title and background); wherein BYL719 was administered QD in 28-day cycles as whole tablets (Methods); patients treated with BYL719 300 mg QD or 400 mg QD (Results); and combination comprising BYL719 was tolerated and demonstrated encouraging antitumor activity (Conclusions). Thus, Razak teaches administering alpelisib orally. QD reads on once per day.
It would have been prima facie obvious to one of ordinary skill in the art to utilize the amounts and treatment regimens of alpelisib taught by Razak as a starting point to optimize the amount and dosing regimen of alpelisib used in combination with tipifarnib to treat HNSCC since Razak teaches amounts of alpelisib used in combination treatment for treating HNSCC and because dosage and treatment regimen are result-effective variables, i.e., a variable that achieves a recognized result. It would have been prima facie obvious to one of ordinary skill in the art to arrive at the method of the instant claims in view of the previously allowed claims and Razak.
Response to Arguments
Applicant’s request for maintaining the rejection on the grounds of non-statutory obviousness-type double patenting over US Patent No. 11,672,774 is noncompliant with the regulations under 37 C.F.R. 1.111. The instant rejection is not a provisional rejection as the claims of US Patent 11,672,774 have been issued. In the interest of compact prosecution, the examiner has examined the instant application. However, in order for the response to the instant Office Action to be fully responsive and in compliance with the regulations under 37 C.F.R. 1.111, the Applicant should either file a terminal disclosure or traverse the rejection based on US Patent No. 11,672,774. Because applicant did not distinctly and specifically point out the supposed errors in the instant non-statutory obviousness-type double patent rejection in view of US Patent No. 11,672,774 and no Terminal Disclaimer has been filed, the rejection is maintained.
Conclusion
Claims 1-5, 8-10, 12-14, 17-21, 28, 33, 35-39, and 42-44 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Rayna Rodriguez/Primary Examiner, Art Unit 1628
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