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 .
Priority
This application is a CON of 17/488,194 (09/28/2021, now US11672774),
17/488,194 is a CON of PCT/US2020/025149 03/27/2020
PCT/US2020/025149 has PRO 62/922,749 08/27/2019 *
PCT/US2020/025149 has PRO 62/826,771 03/29/2019
(*) Data provided by applicant is not consistent with PTO record
The domestic benefit part of the ADS has a typo with 62/922749 – see first page of the specification with correct 62/992749.
In order to receive benefit of the earlier priority claim, appropriate correction is required.
Status
Rejections not reiterated in this action are withdrawn.
Claims 1, 15, 18-20, 37-40, 43, 45, 53, 55, 63-67. Claims 66-67 were newly presented.
New 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 64 is 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.
Claim 64 uses “for example” in the claim which renders the claim indefinite. See MPEP 2173.05(d) (“Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph should be made.”).
New 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 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, 15, 18-20, 37-40, 43, 45, 53, 64-67 are rejected under 35 U.S.C. 103 as being unpatentable over Gualberto et al. (WO2018085518).
Regarding claim 1, Gualberto teaches a method of treating HNSCC in a subject comprising administering a therapeutically effective amount of tipifarnib (claim 12; [0029]: “In some embodiments, the cancer is head and neck squamous cell carcinoma (HNSCC)”; [0687]: “In some embodiments, provided herein is a method of treating a HNSCC in a subject with tipifarnib”; claim 1: “administering a therapeutically effective amount of a farnesyltransferase inhibitor (FTI) to said subject”, claim 122: “wherein the FTI is tipifarnib”). Gualberto teaches the method of treatment includes administering a second agent, including embodiments of a CDK inhibitor palbociclib ([00137]; [00259]: “In some embodiments, the methods further comprise administering a second therapy to the patient having SCCHN … In some embodiments, the second therapy include those targeting … CDK4/6-cell cycle pathway: Palbociclib”). Gualberto does not specifically teach claim 1’s language related to wild-type H-Ras-overexpressing HNSCC.
Gualberto teaches [0100]: “cancer patients who have wild type K-Ras and N-Ras are more sensitive to FTI treatment compared to those who have a mutant K-Ras or N-Ras, and that selection of cancer patients based on the Ras mutation status can improve the overall response rate of an FTI treatment, such as a tipifarnib treatment”. However, one of ordinary skill in the art would have understood, and based on the teaching on Gualberto, that the mechanism of action of tipifarnib is such that it prevents H-Ras membrane localization and would inhibit H-Ras-driven oncogenic transformation ([0639] “FTIs such as tipifarnib prevent protein farnesylation, a type of protein modification known as prenylation, which along with other protein modifications, allows membrane localization of H-ras where it can receive and transmit extracellular signals implicated in cancer initiation and development. FTIs such as tipifarnib can block H-ras farnesylation and subsequent membrane localization, and inhibit oncogenic, H-ras-driven cellular transformation in vitro and in vivo.”). One of ordinary skill in the art would have considered the use of the term “Ras mutation” as including phenotypes including activation of wild-type H-Ras or even a copy of the wild-type H-Ras ([0100] “As used herein, the term “Ras mutation” refers to an activation mutation in a ras gene or Ras protein”, “As used herein, a sample or a subject having a Ras mutation can also have a copy of wild type ras gene and/or the wild type Ras protein” ; [0638]: “H-ras acts as a molecular on/off switch—once it is turned on it recruits and activates proteins necessary for the propagation of the receptor's signal. In certain tumors, mutations in H-ras or its upstream effectors cause it to be permanently on, resulting in persistent activation of downstream growth and proliferation signals that drive tumor cell growth. FTIs work to prevent the aberrant growth and proliferation of cells that are dependent on these signaling pathways by inhibiting protein farnesylation and subsequent membrane localization of H-ras, thereby switching H-ras off.”), leading to overexpression of H-Ras. Based on the teaching of Gualberto, one of ordinary skill in the art would have reasonably considered that cancers with overexpression of H-Ras, including a copy of the wild-type, would have been successfully treated in the same manner due to the known mechanism of action of tipifarnib blocking farnesylation and ultimately oncogenesis.
Regarding claim 15, Gualberto teaches “wherein the SCCHN is SCCHN of the oral cavity” (claim 10).
Regarding claim 18, Gualberto teaches “wherein said SCCHN is HPV negative” (claim 5).
Regarding claim 19, Gualberto teaches “A method of treating EGFR inhibitor-refractory squamous cell carcinoma of the head and neck (SCCHN) in a subject” (claim 1).
Regarding claim 20, Gualberto teaches the SCC is metastatic (claim 6).
Regarding claims 37-39, Gualberto teaches “In some embodiments, tipifarnib is administered at a dose of 200-1200 mg twice a day ("b.i.d.")” ([0018]).
Regarding claims 40 and 43, Gualberto teaches “tipifarnib is administered at a dose of 300 mg b.i.d. orally in alternate weeks (days 1-7 and 15-21 of repeated 28-day cycles)” ([0018]).
Regarding claim 45, Gualberto teaches “the FTI treatment is administered in combination with radiotherapy, or radiation therapy” ([00130]).
Regarding claim 53, Gualberto teaches the second agent is a CDK inhibitor, palbociclib ([00259]).
Regarding claim 64, Gualberto teaches administration of tipifarnib with cetuximab (claim 30).
Regarding claim 65, Gualberto teaches the SCC “overexpresses the HRAS mRNA and/or protein” ([0004]).
Regarding claim 66, Gualberto does not specifically teach wherein the HNSCC has wild-type H-Ras overexpression that is greater than a reference level; wherein the reference level is a median expression level of wild-type H-Ras in corresponding tissue in a population of healthy subjects or a median expression level of wild-type H-Ras in corresponding tissue in a population of HNSCC subjects. However, Gualberto does teach “reference expression levels of a biomarker” ([0088]: “A reference expression level of a biomarker can be the expression level of the biomarker in a sample from a healthy individual. A reference expression level of a biomarker can also be a cut-off value determined by a person of ordinary skill in the art through statistic analysis of the expression levels of the biomarker in a sample population and the responsiveness to a treatment of the individuals in the sample population.”) and that the activated Ras pathway serves as a “biomarker” ([0099]: “constitutively active RAS pathway can serve as a biomarker for patient response to FTIs”) which one of ordinary skill in the art would have considered in combination with their ordinary skill and experience to compare the identified biomarker H-Ras to a median expression level from statistical analysis of biomarkers in relevant populations and arrive at the claimed invention.
Regarding claim 67 Gualberto teaches overexpression includes increased transcription and translation ([0032]).
With each of the above claims, the level of skill in the art is very high such that one of ordinary skill in the art would consider routine the combination of elements from the teaching of the art. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known combinations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed with a reasonable expectation of success before the effective filing date of the claimed invention.
Claims 55 and 63 are rejected are rejected under 35 U.S.C. 103 as being unpatentable over Gualberto et al. (WO2018085518) as applied to claims 1, 15, 18-20, 37-40, 43, 45, 53, 64-67 above and further in view of Dienstmann et al. (Mol Cancer Ther (2014) 13 (5): 1021–1031).
Regarding claim 55 and 63, Gualberto teaches the second agent is a PI3K-a inhibitor ([00259]), while Dienstmann teaches MK-2206 and INK-128 are AKT/PI3K inhibitors in clinical development as cancer therapeutics(Table 1).
Regarding claimed combinations of tipifarnib with a second agent, Gualberto teaches administering combinations of a farnesyltransferase inhibitor, such as tipifarnib, with a second active agent ([0693]: “In some embodiments, the methods further comprise administering a second therapy to the patient having a solid tumor with a H-Ras mutation.”; [0765]: “If a tipifarnib treatment is prescribed to the patient, the patient can simultaneously receive another treatment, such as ionizing radiation, or a second active agent or a support care therapy, as deemed fit by the oncologist. In a head and neck squamous carcinoma patient, the additional treatment can be an anti-EGFR antibody treatment, an anti-PD1/PDL1 treatment.”). Regarding the selection of the second agent, Gualberto teaches that the second agent / therapy include those targeting the PI3K pathway ([0693] “In some embodiments, the methods further comprise administering a second therapy to the patient having a solid tumor with a H-Ras mutation. … In some embodiments, the second therapy include those targeting PI3K pathway”). One of ordinary skill in the art would have considered such a combination because Gualberto specifically suggests it. Thus, one of ordinary skill in the art would have a reasonable expectation of arriving at the claimed invention.
Furthermore, the combination of two anticancer agents for the same purpose is prima facie obvious. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 126 USPQ 186 (CCPA 1960) (the “joint use [of magnesium oxide and calcium carbide] is not patentable” where the prior art teaches “that both magnesium oxide and calcium carbide, individually, promote the formation of a nodular structure in cast iron, and it would be natural to suppose that, in combination, they would produce the same effect and would supplement each other”); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
See also Merck & Co., Inc. v. Biocraft Labs, Inc., 874 F.2d 804, 808 (Fed. Cir. 1989) (“Given the prior art teaching that both amiloride and hydrochlorothiazide are natriuretic, it is to be expected that their coadministration would induce more sodium excretion than would either diuretic alone”); In re Diamond, 360 F.2d 214, 217 (CCPA 1966) (where the evidence showed that synergy was expected because combined drugs targeted different cellular mechanisms, and no evidence to the contrary was produced, “[w]e are not convinced of [the] non-obviousness of the combination of two drugs, A5MP and a glucocorticoid . . . particularly since Appeal the record supports the [PTO’s] contention that the drugs selected are two of the commonly used drugs in the treatment of such collagen diseases”).
In this case, the FTI and second agent were known as cancer therapies individually, and one of ordinary skill in the art would have known that combinations of tipifarnib with second agents would be successful based on the teaching of Gualberto. Therefore, the combination of the two compounds for the very same purpose is prima facie obvious. “[T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 205 USPQ 1069, 1072 (CCPA 1980).
The Supreme Court stated in KSR "if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person's skill." KSR Intern. Co. v. Teleflex Inc., 127 S.Ct. 1727, 1731 (2007).
Because combining the two anticancer therapies is taught by the prior art and such combinations have been shown to be successful, one of ordinary skill in the art would have a reasonable expectation of success in arriving at the combination as in the claimed invention.
New Double Patenting Rejections
Claims 1, 15, 18-20, 37-40, 43, 45, 53, 55, 63-67 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-50 of U.S. Patent No. 11672774 in view of Gualberto et al. (WO2018085518). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the patent are to a method of treating HNSCC by administering tipifarnib and a second inhibitor which as detailed in the 35 USC 103 rejection above renders the instant claims obvious.
Claims 1, 15, 18-20, 37-40, 43, 45, 53, 55, 63-67 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8-10, 12-14, 17-21, 28, 33, 35-39, 42-44 of copending Application No. 18355850 (reference application) in view of Gualberto et al. (WO2018085518). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference application are to a method of treating HNSCC by administering tipifarnib and a second inhibitor which as detailed in the 35 USC 103 rejection above renders the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
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 ROBERT H HAVLIN whose telephone number is (571)272-9066. The examiner can normally be reached 9am - 6pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney Klinkel can be reached at (571) 270-5293. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ROBERT H HAVLIN/Primary Patent Examiner, Art Unit 1626