DETAILED ACTION
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 .
Status of the Application
This Office Action is in response to applicant’s arguments filed on 1/26/26. Claims 2, 5-6, 13-14, 17-20 have been cancelled. Claims 8 and 16 have been withdrawn. Claims 1, 3-4, 7-12, 15-16 are pending. Claims 1, 3-4, 7, 9-12, 15 are examined herein.
Applicant’s arguments have been fully considered but found not persuasive. The rejection of the last Office Action is maintained for reasons of record and repeated below for Applicant’s convenience.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1, 3-4, 7, 9-12, 15 are rejected under 35 U.S.C. 103 as being unpatentable over Oh et al. (“Identification of Insulin-Like Growth Factor Binding Protein-3 as a Farnesyl Transferase Inhibitor SCH66336-Induced Negative Regulator of Angiogenesis in Head and Neck Squamous Cell Carcinoma" Clin Cancer Res 2006; 12(2), January 15, 2006, of record) in view of Solca et al. (US Patent Application 2013/0004481, of record) and Cox et al. (“Ras history The sage continues,” Small GTPases, 2010, 1:1, 2-17, of record).
The instant claims are directed to a method of treating head and neck squamous cell carcinoma (HNSCC) associated with a mutation of Hras G12V by administering the farnesyltransferase inhibitor (FTI), tipifarnib.
Oh et al. teaches that farnesyl transferase inhibitor (FTI) SCH66336 has been shown to have antitumor activities in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo (abstract). SCH66336 was orally administered at daily doses of 40 mg/kg and 25 mg/kg (page 658, right column, second full paragraph).
However, Oh et al. fail to disclose Hras G12V and tipifarnib.
Solca et al. teach a method of treating cancer by administering MEK inhibitors (abstract), for example adenoid squamous cell carcinoma (paragraph 0286), which is a type of head and neck squamous cell carcinoma. Other anti-cancer agents that can be administered include the Ras-farnesyltransferase inhibitor, tipifarnib (also known as Zarnesta) (paragraphs 0228, 0232). Solca teaches that the cancer patient also has at least one mutation in the Ras gene (claim 5), such as G12V (claim 11), which is detected from a patient derived tumor tissue sample (paragraphs 0116, 0125, 0129, 0182). Doses of the active agents should be in the range of 0.1 to 90 wt%, preferably 0.5 to 50 wt%, and may be administered several times a day (paragraph 0294). Doses for oral use may be from 1-2000 mg per day, for example 50 to 700 mg per day (paragraph 0307). Examples of pharmaceutical formulations include 100, 80, and 50 mg of active substance (Tables A-C in paragraphs 0348-0350).
Cox et al. teaches that activated RAS genes have been detected in a wide spectrum of human tumor cell lines as well as in primary patient tumor material. Most striking was the high frequency of RAS mutations found in colon, lung, and pancreatic cancers. In addition to mutations at codon 12, RAS mutations were later identified at codons 13 and 61. Although mutations affecting other regions of the proteins have been found at very low frequencies, these three codons are the sites of 97–99% of all RAS mutations in cancer (Fig. 4) and thus comprise the three hot spots of Ras activation. Also strikingly, not all Ras isoforms are equally likely to be mutated. Among the RAS isoforms, missense mutations are found most commonly in KRAS (85%), less commonly in NRAS (12%), and rarely in HRAS (3%) (Fig. 4D). Interestingly, the missense mutation frequency at each position varies widely between isoforms, with G12 mutations the most common in KRAS and HRAS, while Q61 mutations are the most common in NRAS (Fig. 4D) (page 5, paragraph bridging left and right columns).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have treated HNSCC having a HRas G12V mutation, as taught by Solca and Cox et al., by administering the FTI, SCH66336, as taught by Oh et al.
A person of ordinary skill in the art would have been motivated to treat HNSCC having a HRas G12V mutation because Oh et al. teaches that HNSCC, in general, can be treated with an FTI. Solca et al. teach that adenoid squamous cell carcinoma, which is a type of head and neck squamous cell carcinoma, can have at least one mutation in the Ras gene, such as G12V. Cox et al. teach that HRAS is one of three known Ras isoforms. Cox et al. also teach that HRAS is one of two isoforms that the G12 mutation is most commonly found in. Therefore, the skilled artisan would have had a reasonable expectation of successfully treating HNSCC with the Hras G12V mutation by administering a FTI, absent a showing of unexpected results.
Therefore, it would also have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have substituted the particular FTI, tipifarnib, as taught by Solca et al., for the FTI, SCH66336, as taught by Oh et al. in the method of treating HNSCC.
A person of ordinary skill in the art would have been motivated to substitute tipifarnib for SCH66336 because both are well-known FTIs, therefore considered functionally equivalent. The skilled artisan would have had a reasonable expectation of success in similarly treating HNSCC with another FTI, such as tipifarnib, as with SCH66336.
It is noted that the limitation regarding “wherein administration of the therapeutically effective amount of FTI monotherapy reduces tumor burden in the subject compared to an untreated control subject suffering from the HNSCC” is considered obvious to occur since this limitation is a result or property of the same claimed patient population being administered the same claimed active agent.
Response to Arguments
Applicant argues that Solca does not teach any FTI monotherapy methods for the purpose of treating HRAS mutant tumors because the sole reference to adenoid cell carcinoma is specifically in context to stomach cancer. Furthermore, Solca cannot teach RAS gene since only NRAS and KRAS is mentioned.
This is not persuasive because this argument is based on the assumption that Solca only refers to NRAS or KRAS mutations, which is incorrect. Although Solca provides NRAS and KRAS as examples of RAS mutations, it is in no way limited to only NRAS and KRAS mutations. Attention is drawn to claims 1 and 2, where RAS mutations are taught, in general. The Cox reference was used to teach that HRAS is one of three known RAS isoforms. Cox also teach that HRAS is one of two isoforms that the G12 mutation is most commonly found in. Therefore, since Solca teach HNSCC with RAS mutations, in general, and Cox teach that HRAS G12V is a specific type of mutation, the instant claims are obvious.
Applicant argues that Solca fails to provide any motivation to select HNSCC cancers out of the 36 different classes of cancers as listed in paragraph 0286 for the treatment with a FTI selected from 44 different functional classes of cotherapies listed in paragraph 0288 having any HRAS mutations. Furthermore, Applicant argues that there is no motivation to remove the MEK inhibitor of Solca to arrive at the claimed FTI monotherapy.
This is not persuasive because Applicant is reminded that the primary reference is Oh, which teaches the use of FTI inhibitor to treat HNSCC. Solca was merely used to teach the limitations regarding mutations.
The Fagin Declaration 2 under 37 CFR 1.132 filed 1/26/26 is insufficient to overcome the rejection of claims 1, 3-4, 7, 9-12, 15 based upon Oh et al. (“Identification of Insulin-Like Growth Factor Binding Protein-3 as a Farnesyl Transferase Inhibitor SCH66336-Induced Negative Regulator of Angiogenesis in Head and Neck Squamous Cell Carcinoma" Clin Cancer Res 2006; 12(2), January 15, 2006, of record) in view of Solca et al. (US Patent Application 2013/0004481, of record) and Cox et al. (“Ras history The sage continues,” Small GTPases, 2010, 1:1, 2-17, of record) as set forth in the last Office action.
The declaration argues that it was recognized in the art that anti-cancer agents that were known to be effective monotherapies in HRAS wild type cancer cell lines were actually ineffective in treating cancer cell lines expressing HRAS mutations. For example, Leiser demonstrates that several MEK inhibitors which were effective in treating HRAS wild type cells, failed to inhibit tumor growth when the same cells were transfected with the HRAS G12V mutation (Figures 5A and 5B).
This is not persuasive because it is not clear how MEK inhibitors are related to this invention. MEK inhibitors are not claimed nor are they related in any way to the claimed FTI monotherapy. Therefore, this argument is irrelevant.
The declaration also argues that constitutively active HRAS mutations were known to confer resistance to monotherapy with anti-cancer agents that were previously shown to be effective in treating HRAS wild-type HNSCC cancer cell lines. For example, Hah et al. teaches that transfection of activating HRAS-mutant G12D and G12V constructs into these sensitive HSNCC cell lines made them more resistant to erlotinib (Figures 3 and 5).
Again, this is not persuasive because it is not clear how erlotinib is related to this invention. Erlotinib is not claimed nor are they related in any way to the claimed FTI monotherapy. Therefore, this argument is irrelevant.
What would be relevant is to see FTI monotherapies, other than the claimed tipifarnib or lonafarnib, being successful in treating wild type HNSCC and ineffective in mutant forms of HNSCC.
Applicant is reminded that Oh teaches treating HNSCC, in general, and that any specific form of HNSCC, including mutated forms, are obvious absent a showing of unexpected results.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 Yong S. Chong whose telephone number is (571)-272-8513. The examiner can normally be reached Monday to Friday: 9 AM to 5 PM EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam Milligan, can be reached at (571)-270-7674. The fax phone number for the organization where this application or proceeding is assigned is (571)-273-8300.
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/Yong S. Chong/Primary Examiner, Art Unit 1623
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