DETAILED ACTION
Claims 1-18 are currently pending and under examination.
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 .
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating or inhibiting proliferation and metastasis of medulloblastoma, does not reasonably provide enablement for treating or inhibiting cancer proliferation and metastasis in any cancer as claimed in the independent claims 1 and 10, or the list of cancers recited in dependent claims 5 and 14. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the Invention: Claims 1-18 are drawn to a method for treating or inhibiting cancer proliferation and metastasis, comprising administering a composition comprising from about 0.0001 mg/kg to about 30mg/kg (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof. However, the nature of the invention is complex in that cancer as claimed in independent claims 1 and 10, or the select list in claims 5 and 14 is beyond the scope of the conditions in which one skilled in the art has been taught to make or use the invention.
Breadth of the Claims: The claims are broad in that the claims recite a method for treating or inhibiting cancer proliferation and metastasis in a wide variety of cancers, comprising administering a composition comprising from about 0.0001 mg/kg to about 30mg/kg (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the Specification and Existence of Working Examples: The specification describes a compound, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, with an identified mechanism of action of GABA-AT inhibition by which select relevant cancer types listed in claims 5 and 14 are stated to be affected. However, the cancer types listed are broad and the references and examples provided are not commensurate with the scope of the claims. The applicant’s mere statement that the cancers recited in claims 5 and 14 are all able to metabolize GABA is not convincing to one skilled in the art, based on a preponderance of the evidence standard. Working examples provide toxicology and pharmacokinetic data, and an outline for proposed future administration in a subject, but as of the effective filling date no working example showing administration of the compound in any subject has been demonstrated. However, the identified mechanism of GABA-AT inhibition through which (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid affects cancer, the identified mechanism of GABA metabolism through which medulloblastoma is stated to proliferate, and the prophetic example in which the compound is tested on a medulloblastoma cell line in subjects, provides sufficient guidance to make and use the claimed method in medulloblastoma.
Predictability and State of the Art: The state of the art at the time the invention was made was unpredictable and underdeveloped. It is known in the art that GABA-AT metabolizes GABA to form metabolites used in energy production, and it has been demonstrated in the art that certain cancers such as medulloblastoma use this metabolic pathway to proliferate. It is also known in the art that the claimed compound, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, has activity as an inhibitor against GABA-AT and has a more favorable pharmacokinetic and toxicologic profile over other relevant compounds in the field. However, it has not been demonstrated that all cancers can use GABA-AT to metabolize GABA as an energy source. Cancer is a highly unpredictable field, with variability in their mechanism of growth, and there is no guarantee that a discovered mechanism in one cancer type will exist in another.
https://ccr.cancer.gov/news/milestones-2018/article/not-all-tumor-cells-are-created-equal explains that the molecular makeup and biological properties of cancer cells can vary significantly.
Amount of Experimentation Necessary: The quantity of experimentation necessary to carry out the claimed invention is high, as the skilled artisan could not rely on the prior art or instant specification to teach a method for treating or inhibiting cancer proliferation and metastasis in any type of cancer, comprising administering a composition comprising from about 0.0001 mg/kg to about 30mg/kg (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof.
In order to carry out the claimed invention, one of ordinary skill in the art would have to determine whether every known cancer type under any condition can metabolize GABA effectively enough as a fuel source to proliferate, such that a GABA-AT inhibitor could effectively inhibit that proliferation.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 1-18 are not considered to be fully enabled by the instant specification.
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.
Claim(s) 1-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over
Juncosa, J.I. (Design and Mechanism of (S)‑3-Amino-4-(difluoromethylenyl) cyclopent-1-ene-1-carboxylic Acid, a Highly Potent γ‑Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Addiction, Journal of the American Chemical Society, Vol. 140, no. 6 (January 30th, 2018), pp. 2151-2164), in view of (Martirosian.V, Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination, Cell Reports, Vol. 35, no. 13 (June 29th, 2021), pp. 1-17).
The following 35 U.S.C. 103 rejection applies to the extent that the Applicant’s claimed invention is drawn to a method of treating or inhibiting proliferation and metastasis of medulloblastoma.
Claim 1 is drawn to a method for inhibiting cancer proliferation and metastasis, comprising administering a composition comprising from about 0.0001 mg/kg to about 30mg/kg (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof.
Claim 2 is drawn to the method of claim 1, wherein the composition comprises from about 0.1 mg/kg to 15 mg/kg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.
Claim 3 is drawn to the method of claim 2, wherein the composition comprises from about 0.2 mg/kg to 10 mg/kg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.
Claim 4 is drawn to the method of claim 3, wherein the composition comprises from about 0.5 mg/kg to 6.5 mg/kg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.
Claim 5 is drawn to the method of claim 1, wherein the cancer is medulloblastoma, glioma, breast cancer, squamous cell cancer, melanoma, lung cancer, cancer of the peritoneum, hepatocellular cancer, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, testicular cancer, bladder cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, hairy cell leukemia, leptomeningeal carcinomatosis, or chronic myeloblastic leukemia and subtypes thereof.
Claim 6 is drawn to the method of claim 1, wherein the subject is human.
Claim 7 is drawn to the method of claim 1, wherein the subject is also undergoing one or more cancer therapies selected from the group consisting of surgery, chemotherapy, radiotherapy, thermotherapy, immunotherapy, hormone therapy, or laser therapy.
Claim 8 is drawn to the method of claim 1, wherein the composition is administered enterally or parenterally.
Claim 9 is drawn to the method of claim 8, wherein the composition is administered orally, rectally, transdermally, intramuscularly, intravenously, subcutaneously, intraperitoneally, or intrathecally.
Claim 10 is drawn to a method for treating cancer, comprising administering a composition comprising from about 0.0001 mg/kg to about 30mg/kg (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, thereby treating the cancer.
Claim 11 is drawn to the method of claim 10, wherein the composition comprises from about 0.1 mg/kg to about 15 mg/kg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.
Claim 12 is drawn to the method of claim 11, wherein the composition comprises from about 0.2 mg/kg to about 10 mg/kg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.
Claim 13 is drawn to the method of claim 12, wherein the composition comprises from about 0.5 mg/kg to about 6.5 mg/kg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.
Claim 14 is drawn to the method of claim 10, wherein the cancer is medulloblastoma, glioma, breast cancer, squamous cell cancer, melanoma, lung cancer, cancer of the peritoneum, hepatocellular cancer, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, testicular cancer, bladder cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, hairy cell leukemia, leptomeningeal carcinomatosis, or chronic myeloblastic leukemia and subtypes thereof.
Claim 15 is drawn to the method of claim 10, wherein the subject is human.
Claim 16 is drawn to the method of claim 10, wherein the subject is also undergoing one or more cancer therapies selected from the group consisting of surgery, chemotherapy, radiotherapy, thermotherapy, immunotherapy, hormone therapy, or laser therapy.
Claim 17 is drawn to the method of claim 10, wherein the composition is administered enterally or parenterally.
Claim 18 is drawn to the method of claim 17, wherein the composition is administered orally, rectally, transdermally, intramuscularly, intravenously, subcutaneously, intraperitoneally, or intrathecally.
Applicant has claimed a subject can be any mammal in need of treatment, and has claimed a broad range of effective dosing without any working example of administering the claimed compound to a subject in need thereof to measure the effect of the claimed compound on cancer cells. Prior art showing efficacy in relevant cell lines, using amounts that would have been routinely optimized to arrive at the applicants claimed effective dosing range, are referred to in this section.
Juncosa teaches that the claimed compound, (S)-3-amino-4-(difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid, has more potency as an inhibitor of GABA-AT as well as a more favorable toxicology profile, than Vigabatrin and CPP-115, two compounds known in the art to share a mechanism of action with the claimed compound (See e.g. Page 2151; Abstract).
Juncosa does not teach how (S)-3-amino-4-(difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid, through its mechanism of action as an inhibitor of GABA-AT, is relevant in affecting medulloblastoma.
Martirosian teaches that medulloblastoma upregulates GABA-AT in nutrient poor conditions of the cerebrospinal fluid to convert GABA into succinate for energy to proliferate and facilitate leptomeningeal metastasis formation (See e.g. Page 1; Summary).
Martirosian also teaches the same human cell line (D283 medulloblastoma cells) that the Applicant used, in mice models (See e.g. Page 13; EXPERIMENTAL MODEL AND SUBJECT DETAILS). The Applicant uses a prospective assessment using this cell line to support claiming a human subject in claims 6 and 15.
It would have been obvious to one having ordinary skill in the arts to combine Juncosa’s teaching that (S)-3-amino-4-(difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid has known inhibitory activity on GABA-AT, with Martirosian’s teaching that medulloblastoma is able to utilize GABA-AT to metabolize GABA as an energy source in human D283 medulloblastoma cells to arrive at the Applicant’s claimed method of treating or inhibiting proliferation and metastasis of medulloblastoma in a subject in need thereof, wherein the subject may be a human.
The various dosing ranges in claims 1, 2, 3, 4, 10, 11, 12, and 13 are obvious as one skilled in the art would have been motivated to routinely optimize the dosing of (S)-3-amino-4-(difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid in a composition used in a method to treat medulloblastoma once the mechanism of GABA-AT was established as a result-effective variable. "[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 7 and 16, requiring the addition of one or more cancer therapies, are obvious as these therapies are known in the art as methods of treating cancer. "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, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Claims 8, 9, 17, and 18, requiring a range of routes of administration for the composition to be administered, are obvious as these are routine routes of administration for pharmaceutical compounds. The Applicant has shown intraperitoneal dosing of the claimed compound, and no evidence to suggest alternate routes of administration would be ineffective, and thus one skilled in the art would have a reasonable expectation of success choosing from a finite number of routine and predictable routes of administration (MPEP 2143(I)(E).
Obviousness can be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so. In re Kahn, 441 F.3d 977, 986, 78 USPQ2d 1329, 1335 (Fed. Cir. 2006) (discussing rationale underlying the motivation-suggestion-teaching test as a guard against using hindsight in an obviousness analysis). Axonics, Inc. v. Medtronic, Inc., 73 F.4th 950, 957-58, 2023 USPQ2d 795 (Fed. Cir. 2023) (the court found an erroneous framing of the motivation inquiry led to an incorrect conclusion of nonobviousness). A "motivation to combine may be found explicitly or implicitly in market forces; design incentives; the ‘interrelated teachings of multiple patents’; ‘any need or problem known in the field of endeavor at the time of invention and addressed by the patent’; and the background knowledge, creativity, and common sense of the person of ordinary skill." Zup v. Nash Mfg., 896 F.3d 1365, 1371, 127 USPQ2d 1423, 1427 (Fed. Cir. 2018) (quoting Plantronics, Inc. v. Aliph, Inc., 724 F.3d 1343, 1354 [107 USPQ2d 1706] (Fed. Cir. 2013) (citing Perfect Web Techs., Inc. v. InfoUSA, Inc., 587 F.3d 1324, 1328 [92 USPQ2d 1849] (Fed. Cir. 2009) (quoting KSR, 550 U.S. at 418-21)). See MPEP § 2143 regarding the need to provide a reasoned explanation even in situations involving common sense or ordinary ingenuity. See also MPEP § 2144.05, subsection II, B.
It would have been obvious to a person having ordinary skill in the art, prior to the effective filling date of the application, to have a reasonable expectation of success of using (S)-3-amino-4-(difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid in a composition to treat medulloblastoma or inhibit medulloblastoma proliferation and metastasis, as the proposed mechanism of action of (S)-3-amino-4-(difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid reducing GABA metabolization through inhibition of GABA-AT was taught in art prior to the effective filling date of the application to affect medulloblastoma.
In the instant case, Juncosa and Martirosian provide adequate teaching, suggestion, or motivation to combine (S)-3-amino-4-(difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid, with its mechanism of action of reducing GABA metabolism through GABA-AT inhibition, along with its favorable potency and toxicologic profile compared to other related compounds, with a method of treating or inhibiting proliferation and metastasis of medulloblastoma through inhibiting GABA metabolism in a subject in need thereof, wherein the subject may be human.
Conclusion
No claims are allowed
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/OROD MOTEVALLI/ Examiner, Art Unit 1628
/AMY L CLARK/ Supervisory Patent Examiner, Art Unit 1628