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 Claims
Claims 1-15 are pending in the instant application.
Domestic Benefit
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/362,684, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Instant Claims 1-12 are drawn to methods comprising administering an SGLT inhibitor and an α-ketoglutarate, EZH2 inhibitor, and/or HIF inhibitor. Combinations with HIF inhibitors are not disclosed in the prior-filed application. Therefore, support for Claims 1-12 is not found in the prior-filed application.
Further, with respect to instant Claims 13-15, the prior-filed application discloses administration of tazemetostat as the EZH2 inhibitor. This is insufficient to support the breadth of EZH2 inhibitors instantly disclosed and encompassed by Claims 13-15. Therefore, Claims 13-15 also fail to find support in the prior-filed application.
Taken together, instant Claims 1-15 do are not supported by the prior-filed application and do not receive the benefit of the filing date of Provisional Application No. 63/362,684 of April 8th, 2022.
The instant application is a national stage entry of the application PCT/US2023/065514, filed April 7th, 2023.
Information Disclosure Statement
The Information Disclosure Statement received January 8th, 2025 has been fully considered by the examiner, except where marked with a strikethrough.
Specification
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. In the instant case, a hyperlink is included at Page 35, Paragraph [0136] and Page 36, Paragraph [0141] of the instant specification.
Appropriate correction is required.
Drawings
Acknowledgement is made of the drawings received October 8th, 2024. These drawings are acceptable.
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 1-15 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 inhibiting the development or progression of a well- or moderately-differentiated adenocarcinoma or for treating adenocarcinoma wherein the adenocarcinoma is adenocarcinoma of the lung comprising administration of an SGLT that is empagliflozin and an inhibitor of EZH2, wherein the EZH2 inhibitor is tazemetostat, does not reasonably provide enablement for inhibiting the development or progression of a pre-malignant lesion or of a well-or moderately-differentiated adenocarcinoma or for the treatment of an adenocarcinoma wherein the adenocarcinoma is adenocarcinoma of tissue other than lung comprising administering any SGLT inhibitor with any α-ketoglutarate, EZH2 inhibitor, and/or HIF inhibitor. 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 and use the invention commensurate in scope with these claims.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to a method of inhibiting the development or progression of a pre-malignant lesion or of a well- or moderately-differentiated adenocarcinoma, or for treating an adenocarcinoma comprising administering an SGLT inhibitor with an α-ketoglutarate, an EZH2 inhibitor, and/or an HIF inhibitor.
Breadth of the invention:
The scope of the claimed invention is very broad, as it is drawn to inhibiting the development or progression of any pre-malignant lesion or of a well- or moderately-differentiated adenocarcinoma, or for treating any adenocarcinoma. This encompasses treatment of adenocarcinoma arising from a myriad of distinct cancers. Further, the method is drawn to administering any SGLT inhibitor with any α-ketoglutarate, EZH2 inhibitor, and/or an HIF inhibitor. This not only includes administration of any SGLT inhibitor, α-ketoglutarate, EZH2 inhibitor, or HIF inhibitor that is known presently, but would also include any SGLT inhibitor, α-ketoglutarate, EZH2 inhibitor, or HIF inhibitor that is discovered years from now. Can Applicant simply “reach through” and obtain patent protection over methods comprising the administration of compounds that have either not yet been discovered or for compounds presently known that are later discovered to fall into one of the aforementioned categories.
State of the prior art and predictability in the art:
No compound has ever been found to treat cancers of all types generally. Since this assertion is contrary to what is known in medicine, proof must be provided that this revolutionary assertion has merits. The existence of such a “silver bullet” is contrary to our present understanding of oncology. The state of the art is not indicative of any pharmaceutical agents that are useful in the treatment of cancer generally. At Page 1004, Cecil Textbook of Medicine states that “each specific type has unique biologic and clinical features that must be appreciated for proper diagnosis, treatment and study”. Different types of cancers affect different organs and have different methods of growth and harm to the body. Also see In re Buting, 163 USPQ 689 (CCPA 1969), wherein ‘evidence involving a single compound and two types of cancer, was held insufficient to establish the utility of the claims directed to disparate types of cancers’. Thus, it is beyond the skill of oncologists today to get an agent to be effective against cancers generally.
A similar statement appears at In re Application of Hozumi et. al., 226 USPQ 353: “In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way”. There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally. This is because it is now understood that there is no “master switch” for cancers generally; cancers arise from a bewildering variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body’s cell growth regulatory mechanisms, but also such external factors such as viruses (an estimated at least 20% are of viral origin e.g. Human papillomavirus, EBV, Hepatitis B and C, HHV-8, HTLV-1 and other retroviruses, and quite possibly Merkel cell polyomavirus, and there is some evidence that CMV is a causative agent in glioblastoma), exposure to chemicals such as tobacco tars, excess alcohol consumption (which causes hepatic cirrhosis, an important cause of HCC), ionizing radiation, and unknown environmental factors.
Similarly, In re Novak, 134 USPQ 335, 337-338 says “unless one with ordinary skill in the art would accept those allegations as obviously valid and correct, it is proper for the examiner to ask for evidence which substantiates them.” There is no such evidence in this case for a compound that treats all types of cancer. Likewise, In re Cartright, 49 USPQ2d 1464, states: “Moreover, we have not been shown that one of ordinary skill would necessarily conclude from the information expressly disclosed by the written description that the active ingredient” does what the specification surmises that it does. That is exactly the case here. Moreover, even if Applicant’s assertion that cancer in general could be treated with these compounds were plausible -- which it is not --, that “plausible” would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success.
Recently, Wu et. al. (“Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA- approved novel therapeutic drugs for solid tumors from 1991 to 2021; Journal of Hematology & Oncology, 15, 143, 2022; hereinafter referred to as Wu), at the Abstract, discloses that between 1991 and 2021 there have been 228 new cancer drugs approved by the U.S. Food and Drug Administration of which 120 of these are drawn to the treatment of solid tumors alone. At Page 5, Table 1 Wu teaches that there are 21 different approved drugs for treating lung cancers, some of which have cellular targets. At Page 10, Table 2, Wu teaches breast cancer has 22 different drugs that have varied cellular targets and are indicated for different types of breast cancer. At Page 17, Table 4, Wu teaches there are 17 different drugs available to treat different forms of gastrointestinal cancers. At Page 38, Figure 12, Wu summarizes the protein structure of some cellular targets and the binding site of their respective drugs. Taken together, Wu teaches that no single therapeutic has ever been identified as a treatment for all forms of cancer; and closer examination of Figure 12 provides a logical explanation. As highlighted in Figure 12, molecular protein targets implicated in different cancers (e.g. EGFR for lung cancer in Table 1, VEGFR2 for gastric cancer in Table 4) have different three-dimensional protein structures, different active sites, and therefore require different drugs with the right shape and chemical groups in order to bind the target active site and have an effect in treating cancer. In other words, there is no one size fits all approach to treating cancer simply for the reason that no single molecule will have the shape and chemical functional groups necessary to bind and modulate all modular targets of cancer, all of which have varied shapes. It is commonly known in the pharmaceutical arts that shape dictates function wherein drugs which have a shape complimentary to the protein target will bind and have an effect (this is often referred to simplistically as a “Lock and Key” model). Given the varied shape of protein targets in cancer (e.g. EGFR and VEGFR2), it is pure fantasy to speculate that a single drug with a single three dimensional shape will bind all protein targets implicated in cancer therapy and have an effect in treating all forms of the disease. As such, at present the “silver bullet” drug therapy to treat all forms of cancer is elusive and such a therapy is not recognized in the art where the reality is that different forms of cancer require different drug therapies.
Level of ordinary skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing chemical compounds for particular activities. The synthesis of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can be employed, developing a therapeutic method, as claimed, prior to synthesizing and testing compounds is generally not well-known or routine, given the complexity of certain biological systems.
The amount of direction provided and working examples:
Beginning at Page 11, several examples are disclosed with respect to studying the progression of cancer arising from lung adenocarcinoma cells. At Page 12, Lines 1-3, Applicant states, “The complex adaptations induced in cancer cells by glucose restriction are not known. Here, we report the discovery that glucose restriction induces de-differentiation and promotes aggression of lung adenocarcinoma (LUAD) cells.
Beginning at Page 12, Example 2 discloses administration of empagliflozin, an SGLT2 inhibitor, to demonstrate glucose restriction induced by SGLT2 inhibition resulted in tumors of poorly differentiated phenotypes.
Beginning at Page 15, Example 3, Applicant discloses an experiment in which 2953A cells were incubated in either high or low glucose levels. Low-glucose growing cells were injected into syngeneic mice, and ultimately treated with empagliflozin. This experiment demonstrates glucose starvation slows tumor growth for reduced proliferation, but eventually induces a more aggressive phenotype in LUAD cells.
Beginning at Page 16, Example 4 discloses data to support that KP mice treated with empagliflozin and tazemetostat reduced tumor burden.
Ultimately, taken together, Examples 1-8 support a novel mechanism indicating glucose restriction induces de-differentiation and increases aggressiveness of LUAD cells.
In terms of combination therapy as required by the instant method, Page 31, Paragraph [0100] describes the method by which mice were treated with empagliflozin and tazemetostat.
No examples demonstrating treatment comprising administering an SGLT inhibitor other than empagliflozin or EZH2 inhibitor other than tazemetostat is described. Due to the unpredictability of treating cancers, as noted above, such limited examples are insufficient to provide enabling disclosure for the breadth of treatment options instantly recited.
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. As referenced above, the examples disclosed instantly are drawn to cells and/or tissues deriving from lung adenocarcinoma. In terms of the administered compounds, the only combination disclosed is a combination of the SGLT inhibitor empagliflozin with the EZH2 inhibitor tazemetostat. Therefore, practice of the breadth of the invention would require a person having ordinary skill in the art not only to identify and/or develop methods to determine the result of administering any of the myriad of possible combinations of compounds, but also to understand the result in tissues and adenocarcinoma not derived from lung adenocarcinoma cells. Practice of this invention beyond the scope of administration of empagliflozin and tazemetostat in for the inhibition and/or treatment of lung adenocarcinoma can not be undertaken with reasonable expectation of success based on the content of the instant disclosure.
Genentech Inc. v Novo Nordisk A/S (CAFC) 42 USPq2d 1001 states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent protection is granted in return for enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person having ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention as noted above.
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 1-3, 5-8, and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Scafoglio et. al. (“Sodium-Glucose Transporter 2 is a diagnostic and therapeutic target for earlystage lung adenocarcinoma”, Sci Transl Med, 2018; hereinafter referred to as Scafoglio 1) in view of Ribich (WO 2018/144798; hereinafter referred to as Ribich).
Regarding Claims 1-3 and 13-15, at Page 2, at the Abstract, Scafoglio 1 teaches SGLT2 is expressed in pre-malignant lesions and well-differentiated adenocarcinomas. Further at the Abstract, Scafoglio 1 teaches targeting SGLT2 with gliflozins reduced tumor growth, and that targeting SGLT2 in lung tumors can intercept lung cancer progression at early stages of development.
With respect to Claim 5, Scafoglio 1 teaches at Page 2, last paragraph that atypical adenomatous hyperplasia (AAH) is known to be a pre-malignant lesion that is a precursor to lung adenocarcinoma, and AAH can progress to adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA).
Regarding Claim 6-7, at Page 11, Second Paragraph, Scafoglio 1 teaches SGLT2 inhibitors hinder tumor progression. Further, it is taught that canagliflozin, as recited at Claim 7, resulted in tumor volume fold decrease after treatment.
Scafoglio 1 does not teach administration of am SGLT inhibitor with an α-ketoglutarate, EZH2 inhibitor, or HIF inhibitor.
At Page 34, Paragraph [00134], Ribich teaches a method for treating a cell proliferative disorder comprising administering an EZH2 inhibitor that is tazemetostat. Further, at Paragraph [00135], Ribich teaches the cell proliferative disorder is lung cancer. At Page 3, Paragraph [006], Ribich teaches the lung cancer can be adenocarcinoma.
Regarding Claims 10-11, at Page 84, Paragraph [00259], Ribich teaches tazemetozab can be administered as a pharmaceutical composition, administered intranasally in the form of a spray.
Regarding Claim 12, at Page 91, Paragraph [00285], Ribich teaches the aforementioned method is useful in treating humans.
Taken together, Scafoglio 1 and Ribich establish administration of canagliflozin and tazemetostat, respectively, as being useful in treating a lung adenocarcinoma. It would therefore be prima facie obvious to a person having ordinary skill in the art to attempt administration of a combination of canagliflozin and tazemetostat. Per MPEP 2144.06, I., “"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)”. Therefore, the practice of Claims 1-3, 5-8, and 10-15 would have been undertaken with reasonable expectation of success.
Claims 1-7 and 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over Scafoglio et. al. (WO 2021/086962; priority date of October 28th, 2019; cited on Applicant’s Information Disclosure Statement received January 8th, 2025; hereinafter referred to as Scafoglio 2) in view of Aquino-Galvez et. al. (“Effects of 2-methoxyestradiol on apoptosis and HIF-1α and HIF-2α expression in lung cancer cells under normoxia and hypoxia”, Oncology Reports, 2016; hereinafter referred to as Aquino-Galvez) as evidenced by CAS Registry File 362-07-2 (entered into STN November 16th, 1984; hereinafter referred to as CAS Registry File).
Regarding Claims 1-7, at Page 2, Paragraph [0006], Scafoglio 2 teaches methods for treatment of pre-malignant lesions. Further, at Page 3, Paragraph [0009], it is taught such lesions can be lung lesion comprising atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ, invasive adenocarcinoma, and/or minimally invasive adenocarcinoma. Further, the lesion is taught to be prostate, bladder, breast, or pancreatic lesion. At Page 3, Paragraph [0010], it is taught that a method of inhibiting the development or progression of such a pre-malignant lesion is achieved by administering an inhibitor that is a gliflozin, wherein the gliflozin is dapagliflozin, canagliflozin, empagliflozin, or ertrugliflozin.
Regarding Claims 10-11, Scafoglio 2 teaches aerosol administration at Page 5, Paragraph [0021].
Regarding Claim 12, at Page 5, Paragraph [0023], Scafoglio 2 teaches the subject treated can be a human.
Scafoglio 2 does not teach administration of a gliflozin in combination with an HIF inhibitor.
CAS Registry File teaches panzem, recited as an HIF inhibitor instantly, for example, at Claim 9, is also referred to by the name 2-methoxyestradiol.
At Page 582, First Paragraph of the Left Column, Aquino-Galvez teaches dose-dependent inhibition of cell growth of human adenocarcinoma cells in a lung cancer cell line. At the second paragraph of the left column, it is taught that 2-methoxyestradiol is effective as an antimetastatic agent and could be used in combination with other therapeutic agents.
Taken together, Scafoglio 2 and Aquino-Galvez establish the use of glifozins and 2-methoxyestradiol, an HIF inhibitor, respectively in the use of treating a lung adenocarcinoma. In fact, Aquino-Galves further suggests the use of 2-methoxyestradiol in combination therapy. Therefore, a person having ordinary skill in the art would have found it prima facie obvious to attempt administering a combination of a gliflozin, as taught by Scafoglio 2 with 2-methoxyestradiol, as taught by Aquino-Galvez, with reasonable expectation of success. Per MPEP 2144.06, I., “"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)”. Therefore, the practice of Claims 1-3, 5-8, and 10-12 would have been undertaken with reasonable expectation of success.
Conclusion
Claims 1-15 are rejected.
No claim is allowed.
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/D.J.B./Examiner, Art Unit 1624
/BRENDA L COLEMAN/Primary Examiner, Art Unit 1624
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