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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/10/2025 has been entered.
Status of the Claims
Currently, claims 90-106 are pending in the instant application.
Specification Objections – Withdrawn
Objections to Specification:
In light of Applicant’s amendment to the specification, the objections are hereby withdrawn. Browser executable code has been removed.
Claim Rejections - 35 USC § 103 – Maintained
Claim(s) 90-101 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tsang (previously referenced).
Claim(s) 102 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tsang in view of Feuerecker (previously referenced).
Claim(s) 103 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tsang in view of Wilken (previously referenced).
Claim(s) 104 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tsang in view of Cutando (previously referenced).
Response to Applicant Remarks:
Applicant’s arguments are not persuasive, the rejections are hereby maintained. Applicant contends that the claims of the instant application are non-obvious over Tsang. Applicant’s reasoning for non-obviousness are generally drawn to the following:
Tsang provides a plethora of possible immunological and chemotherapeutic agents, when in combination, creates a large amount of possible configurations. Tsang does not explicitly provide an exemplary combination comprising each of the recited components of claim 90 (Remarks page 1, paragraph 1). The teachings of Tsang would not motivate a person or ordinary skill in the art to select the individual recited components of claim 90.
Tsang teaches the administration of metformin prior to the administration of a chemotherapeutic agent (Remarks page 1, paragraph 2).
With regards to element (i), Applicant alleges that the teachings of Tsang would provide no motivation for a person of ordinary skill in the art to arrive at the composition of claim 90. Applicant cites Tsang, wherein Tsang provides multiple alternates for chemotherapeutic agents, immunotherapeutic agents, and glycolysis inhibitors. Applicant contends that because Tsang teaches various alternates of each of these classes of compounds, that the exceedingly large amount of possible combinations (over 223,008 combinations per Applicant’s remarks) of agents would make it infeasible to narrow the combination to the combination of specific components as recited in claim 90. Applicant further alleges non-obviousness on the basis that the teachings of Tsang do not provide an exemplary formulation that contains each of the recited components. Examiner only agrees to the extent that Tsang does not explicitly teach an exemplary formulation containing each of the recited components of claim 90. However, Applicant’s reading of Tsang appears to focus too narrowly on the explicit exemplary formulations, while discarding the value of its teachings as a whole. Tsang explicitly teaches each of genistein, ALA, metformin, and cyclophosphamide, wherein genistein is a glycolysis inhibitor, ALA is an immunological agent, metformin, is an immunological agent, and cyclophosphamide is a chemotherapeutic agent. Tsang further indicates that their invention is drawn to combinations of one or more chemotherapeutic agents and one or more immunological agents. The teachings of Tsang however, do not stop at simply listing possible agents to include in composition, but provide predictable function for each of the components. As previously discussed in the rejection of claim 90 (Non-Final Rejection 06/17/2024), Tsang teaches the mechanics of combined chemo-immunotherapy resulting from the combination of chemotherapeutic agents, immunotherapeutic agents, and glycolysis inhibitors, wherein ATP is downregulated and diminishes the function of the target cell to expel exogenous drug from the cell (specification [0016]). While Tsang may list various alternate species of chemotherapeutic agents, immunological agents, and glycolysis inhibitors, the existence of these alternates, and possible combinations of these alternates do not diminish the obviousness of the combination of the aforementioned components, especially when the teachings of the prior art provide the reasonable expectation of predictable results (i.e., the treatment of cancer).
With regards to element (ii), Applicant contends that Tsang teaches away from the instant invention because Tsang teaches that metformin is administered separately and prior to treatment with a chemotherapeutic agent. The relevant citation of Tsang may be found in paragraph [0080] which is reproduced below for ceonvenience:
“In other embodiments, a metabolic targeting chemotherapy treatment regimen for treating cancer may include a combination therapy, which affects multiple aspects of metabolism and provides synergistic efficacy not seen with individual compounds or treatments. The combination therapy includes administering an effective amount insulin to lower blood glucose and also administering an effective amount of metformin, both of which will inhibit glycolysis by limiting the supply of glucose and inhibiting pro-glycolysis signaling, respectively. Alternatively, the combination therapy includes administering an effective amount of metformin alone prior to treatment with a chemotherapeutic agent. In some embodiments, the administration of metformin may be continued after the administration of the chemotherapeutic agent is stopped or finished. Further, in one embodiment, the methods described herein may include administration of insulin or an insulin-dependent agent to induce hypoglycemia, followed by administration of metformin concurrently with one or more chemotherapeutic agents. The administration may be continued after the administration of the one or more chemotherapeutic agents has been stopped.”
While Applicant is not explicitly incorrect in stating that Tsang teaches the administration of metformin prior to chemotherapeutic agent, it is apparent in the excerpt above that Tsang also teaches or reasonably suggests the administration of metformin concurrently with chemotherapeutic agents after prior insulin treatment. As Tsang indicates that the administration of metformin may be conducted alongside chemotherapeutic agents, it would make obvious a composition comprising metformin alongside the one or more chemotherapeutic agents and one or more immunological agents taught by Tsang.
Claim Rejections - 35 USC § 112 First Paragraph – New Grounds of Rejection
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 105-106 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 the treatment of , does not reasonably provide enablement for the treatment of leiomyosarcoma and ovarian cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make use of the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. See Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
(A) The breadth of the claims:
Claim 105 recites a “method comprising administering the pharmaceutical composition of claim 90 to a subject having cancer”, while claim 106 recites a “method comprising administering the combination therapy of claim 104 to a subject having cancer”. Essentially, each of the aforementioned claims is reciting a method of treating “cancer”. The recitation of each of these claims would encompass the treatment of any and all possible cancers and cancer subtypes, as well as administration to any subjects having any and all possible cancers and cancer subtypes.
(B) The nature of the invention:
The instant invention is drawn to the treatment of cancer by administration of a pharmaceutical composition (claim 105), or the administration of a combination of cancer therapies (claim 106). The pharmaceutical composition being administered is a combination of components comprising genistein, alpha lipoic acid (ALA), metformin, and cyclophosphamide. The combination of therapies comprises the aforementioned pharmaceutical composition, curcumin, genistein, melatonin, and naltrexone.
(C) The state of the prior art:
Cancer pathology and etiology encompasses an extremely wide variety of conditions, localized to different parts of the body. Some non-limiting examples include leukemias, brain cancer, lung cancer, epithelial cancer, metastatic cancers, and benign cancers. As the number of conditions under the umbrella of cancer are varied and numerous, a treatment for one type of cancer may not be effective for another type of cancer. For instance, Wei (Human Gene Therapy 5:969-978 (August 1994)) indicates that cyclophosphamide is an effective chemotherapy for the treatment of tumors involving liver specific enzyme cytochrome P450, as such enzymes activate cyclophosphamide by conversion into cytotoxic metabolites (page 970)1, however is largely ineffective for the treatment of CNS tumors due to said metabolites having limited ability to cross the blood brain barrier and low levels of cytochrome P450 in the brain (page 970)2.
(D) The level of one of ordinary skill in the art:
One of ordinary skill in the art would be considered to be an individual having an understanding of the practices of pharmacology and oncology.
(E) The level of predictability in the art:
As indicated previously, cancers encompass a wide variety of conditions and subtypes, wherein certain treatments for specific cancers may or may not be effective for the treatment of other cancers, and treatments may not provide uniform results across types and subtypes. As previously stated, Wei indicates that cyclophosphamide is largely ineffective in the treatment of CNS tumors. However, Bottom (Journal of Neuro-Oncology 46: 151–156, 2000) indicates the use of high doses of cyclophosphamide in treating pediatric brain tumors. In particular, Bottom found that out of 14 pediatric patients with newly diagnosed glioblastoma multiforme (GBM), three provided complete response, three provided stable disease, and 8 provided progressive disease when provided a regimen of high dose cyclophosphamide. Bottom provides that such results indicate that the use of high dose cyclophosphamide has moderate activity against pediatric GBM (page 151, Abstract)3. As can be seen from both Wei and Bottom, the treatment of cancers is far from a one size fits all method of treatment.
(F) and (G) The amount of direction provided by the inventor and the existence of working examples:
Applicant provides guidance in the form of working examples which exemplify the treatment of leiomyosarcoma (LMS) and ovarian cancer. In particular, working example 7 (specification [00290]-[00295]) indicates the administration of the following composition to a patient suffering from LMS:
PNG
media_image1.png
254
429
media_image1.png
Greyscale
Working example 8 (specification [00296]-[00304]) indicates the administration of the following composition to a subject suffering from ovarian cancer:
PNG
media_image2.png
276
420
media_image2.png
Greyscale
PNG
media_image3.png
274
427
media_image3.png
Greyscale
Working example 9 (specification [00305]-[00311]) indicates the administration of the following composition to a patient suffering from advanced stage IV leiomyosarcoma:
PNG
media_image4.png
249
423
media_image4.png
Greyscale
Working example 10 (specification [00312]-[00321]) indicates the administration of the following composition to a patient suffering from retroperitoneal leiomyosarcoma:
PNG
media_image5.png
202
422
media_image5.png
Greyscale
PNG
media_image6.png
63
429
media_image6.png
Greyscale
The above working examples 7-10 provide guidance with regards to treating leiomyosarcoma or ovarian cancer using compositions or therapy combinations comprising each of the components recited in claims 90 and 104. Applicant has not provided any further examples or guidance with regards to the treatment of any other possible cancers.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
Currently, claims 105-106 encompass the treatment of any and all cancers, while Applicant’s disclosure is only enabling for the treatment of leiomyosarcoma or ovarian cancer. The quantity of experimentation needed to cover the scope of the currently recited claims would be enormous and unfeasible for a person of ordinary skill in the art, as the indicated pharmaceutical composition or combination therapy would need to be administered to subjects suffering from nearly all types of cancers. Such a wide range of treatments have not been demonstrated in the provided disclosure.
Conclusion
Claims 90-106 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC TRAN whose telephone number is (571)272-7854. The examiner can normally be reached Mon-Fri 8:00-5:00.
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, Jeffrey S Lundgren can be reached at (571) 272-5541. 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.
/ERIC TRAN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 “Cyclophosphamide (CPA) is a mainstay for chemotherapy for several types of tumor (Colvin, 1993). This inactive prodrug re-quires bioactivation by liver-specific enzymes of the cytochromeP450 family. One of these, cytochrome P450 231, which is induced by phenobarbital, activates C P A with high efficiency(Clarke and W a x m a n , 1989). The primary metabolite, 4-hydroxy-cyclophosphamide, is unstable and spontaneously decomposes into cytotoxic compounds: acrolein and phosphoramide mustard(Colvin and Hilton, 1981; Sladek, 1987). The latter causes inter-strand cross-links in D N A regardless of cell-cycle phase. Maxi-m u m cytotoxicity is obtained during subsequent S and mitotic (M)phases of the cell cycle due to strand breaks (Colvin, 1993)”
2 “The efficacy of cyclophosphamide in treating tumors of the central nervous system has been limited by the poor transport of the activated metabolites across the blood-brain barrier and into cells (Genka et al, 1990) and by very low levels of cytochromeP450 in the brain and tumor cells (Hodgson et al., 1993)”
3 “Cyclophosphamide is an alkylating agent that has shown activity in the treatment of pediatric brain tumors, including high-grade gliomas. This study was designed to evaluate the response of patients with newly diagnosed glioblastoma multiforme to pre-radiotherapy cyclophosphamide. Fourteen patients with glioblastoma multiforme were treated with high-dose cyclophosphamide (2g/m2/day for 2 doses every 28 days) followed by either sargramostim or filgrastin… Three patients demonstrated complete response; 3 stable disease; and 8 progressive disease. The most common toxicity was hematologic, requiring platelet and packed red blood cell transfusions, with 13 admissions for neutropenia with fever. There were no deaths related to infection or bleeding. These results suggest that high-dose cyclophosphamide has modest activity with acceptable toxicity against newly diagnosed glioblastoma multiforme.”
Prosecution Insights