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 .
Election/Restrictions
Applicant's election with traverse of dihomo-gamma-linolenic acid (DGLA); a solid tumor; muscle atrophy and decreased muscle strength; cancer treatment-related disabilities including atrophy and fibrosis in tissues; and chronic obstructive pulmonary disease (COPD) in the reply filed on 11/14/2025 is acknowledged. The traversal is on the ground(s) that no serious burden would exist on the Examiner to examine all species of claims 88-119. This is not found persuasive because the diseases listed in the instant claims vary greatly in their etiology, patient population, and methods of treatment. Moreover, an individual with a solid tumor would not necessarily overlap with an individual with COPD when searching the claims. The agents of the instant claims (DGLA, GLA, and a D5d inhibitor) additionally differ in their structures and functions, wherein DGLA and GLA are fatty acids while D5D inhibitors are small organic molecules containing heterocyclic rings. A search for DGLA would not necessarily overlap in scope with a search for a D5D inhibitor. Examiner therefore would expect the burden of searching the full scope of the claims to be great. For these reasons, the requirement is maintained.
The requirement is still deemed proper and is therefore made FINAL.
Claims 99-100 and 108-111 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/14/2025. Claims 88-98, 101-107, and 112-119 are examined herein.
Priority
Examiner acknowledges that, according to the Filing receipt received 03/13/2024, that the instant application 18/008,135 filed 12/02/2022 is a 371 of PCT/US2021/035271 filed 06/01/2021, which claims benefit of U.S. provisional applications 63/148,094 filed 02/10/2021 and 63/033,739 filed 06/02/2020.
Information Disclosure Statement
The Information Disclosure Statements filed on 01/19/2024 and 09/11/2024 are in compliance with the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of list of references cited from the IDS is included with this Office Action.
Specification
The disclosure is objected to because of the following informalities:
Par. [0102]: “does not requires… itself be seonlygic” should read “does not require… itself be senolytic”;
Par. [0256]: “shows in Table 2” should read “shown in Table 2”;
Par. [0299]: “polyunsaturaged faty acid” should read “polyunsaturated fatty acid” and “precursonrs” should read “precursors”.
Appropriate correction is required.
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
Claim Objections
Claims 89, 91, 94 is objected to because of the following informalities: Claim 89 is labeled "89," and should read "89."; Claims 91 and 94 recite “cystofbroma” which should read “cystofibroma”; Claims 91 and 94 list “leukemia” twice; Claims 91 and 94 “medulloblastome” should read “medulloblastoma”. Appropriate correction is required.
Drawings
The drawings are objected to because in Fig. 11 the concentration units are listed as "nm" and "μm". Should they read "nM" and "μM"? Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112(b)
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 95, 96, 98, 106, 115, and 119 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 95 recites broader limitations followed by “such as” and/or species placed in parenthesis. The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Moreover, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, each species set forth in parenthesis is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 96 recites “said DNA damaging therapy”. This limitation lacks antecedent basis.
Claim 98 recites “including”. The term “including” causes confusion as it is unclear whether the limitations following the phrase are part of the claimed invention, and/or if the limitations following the phrase are merely exemplary and are not required.
Claim 106 recites “wherein said DGLA is provided as DGLA ethyl ester, DGLA inert lipid, or a combination thereof”. Claims 105 and 88, however, do not include other forms of DGLA in the scope of the claims. These limitations lack antecedent basis.
Claim 115 recites “the drug tamoxifen”. This limitation lacks antecedent basis.
Claim 119 recites “a senolytic agent described in U.S. Patent Publication Nos: US 2019/0022090…”. The claims must be complete in and of themselves where possible. Incorporation by reference of figures/structures/compounds in the claims does not clearly establish the scope of the claims or what compounds are considered to be within the scope of the claims. See MPEP 2173.05(s). Correction is required.
Claim Rejections - 35 USC § 112(a)
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 88-98, 101-107, and 112-119 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 killing senescent cells in a subject with a cancer or pre-cancerous lesions selected from the group consisting of leukemia, acute leukemia, adrenal gland tumor, ameloblastoma, anaplastic carcinoma of the thyroid, angioma, apudoma, argentaffinoma, arrhenoblastoma, ascites tumor, astroblastoma, astrocytoma, ataxia- telangiectasia-associated tumors, basal cell carcinoma, bone cancer, brain tumor, brainstem glioma, breast cancer, Burkitt's lymphoma, cervical cancer, cholangioma, chondroblastoma, chondrosarcoma, chorioblastoma, choriocarcinoma, colon cancer, craniopharyngioma, cystocarcinoma, cystofibroma, cystoma, ductal carcinoma, ductal papilloma, dysgerminoma, encephaloma, endometrial carcinoma, endothelioma, ependymoma, erythroleukemia, Ewing's sarcoma, extra nodal lymphoma, fibro adenoma, fibro sarcoma, follicular cancer of the thyroid, ganglioglioma, gastrinoma cell, glioblastoma multiform, glioma, gonadoblastoma, haemangioblastoma, haemangioendothelioblastoma, haemangioendothelioma, haemangiopericytoma, haematolymphangioma, haemocytoblastoma, haemocytoma, hairy cell leukemia, hamartoma, hepatocarcinoma, hepatocellular carcinoma, hepatoma, histoma, Hodgkin's disease, hypernephroma, infiltrating ductal cell carcinoma, insulinoma, juvenile angioforoma, Kaposi sarcoma, kidney tumor, large cell lymphoma, lipoma, liver cancer, liver metastases, Lucke carcinoma, lung cancer, lymphadenoma, lymphangioma, lymphocytic leukemia, lymphocytic lymphoma, lymphoedema, lymphoeytoma, lymphoma, malignant mesothelioma, malignant teratoma, mastocytoma, medulloblastoma, melanoma, meningioma, mesothelioma, Morton's neuroma, multiple myeloma, myeloid leukemia, myelolipoma, myeloma, myoblastoma, myxoma, nasopharyngeal carcinoma, neuroblastoma, neurofibroma, neuroglioma, neuroma, non-Hodgkin's lymphoma, oligodendroglioma, optic glioma, osteochondroma, osteogenic sarcoma, osteosarcoma, ovarian cancer, pancoast tumor, pancreatic cancer, phaeochromocytoma, plasmacytoma, primary brain tumor, progonoma, prolactinoma, renal cell carcinoma, retinoblastoma, rhabdosarcoma, sarcoma, skin cancer, small cell carcinoma, squamous cell carcinoma, T-cell lymphoma, testicular cancer, thymoma, trophoblastic tumor, and Wilm's tumor; or a pathology characterized by generation of senescent cells and an inflammatory response selected from the group consisting of kyphosis, herniated intervertebral discs, osteoporosis, irritable bowel syndrome, an inflammatory bowel disease, colitis, Crohn's disease, a pulmonary disease, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, bronchiectasis, emphysema, a pathology characterized by fibrosis, renal fibrosis, liver fibrosis, pancreatic fibrosis, cardiac fibrosis, skin wound healing, and oral submucous fibrosis; or a senescence-associated disease or disorder selected from the group consisting of cardiovascular disease; Alzheimer's disease and related dementias, Parkinson's disease; Huntington's disease; mild cognitive impairment; motor neuron dysfunction; cataracts; macular degeneration; glaucoma; presbyopia; atherosclerosis; acute coronary syndrome; myocardial infarction; stroke; hypertension; idiopathic pulmonary fibrosis (IPF); chronic obstructive pulmonary disease (COPD); asthma; cystic fibrosis; emphysema; bronchiectasis; age-related loss of pulmonary function; osteoarthritis; osteoporosis; obesity; fat dysfunction; coronary artery disease; cerebrovascular disease; periodontal disease; cancer treatment-related disabilities including atrophy and fibrosis in tissues, brain and heart injury, or therapy-related myelodysplastic syndromes; an accelerated aging disease including progeroid syndromes, Hutchinson-Gilford progeria syndrome, Werner syndrome, Bloom syndrome, Rothmund-Thomson Syndrome, Cockayne syndrome, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, or restrictive dermopathy; ataxia telangiectasia, Fanconi anemia; Friedreich's ataxia; dyskeratosis congenital; aplastic anemia; IPF; renal dysfunction; renal disease; renal failure; skin wound healing; liver fibrosis; pancreatic fibrosis; oral submucosa fibrosis; inflammatory bowel disease; kyphosis; herniated intervertebral disc; frailty; hair loss; hearing loss; vision loss including blindness or impaired vision; muscle fatigue; diabetes; diabetic ulcer; metabolic syndrome; sarcopenia; sarcopenia oral mucositis; and dermatological conditions including wrinkles, superficial fine wrinkles, hyperpigmentation, scars, keloid, dermatitis, psoriasis, eczema, seborrheic eczema, rosacea, vitiligo, ichthyosis vulgaris, dermatomyositis, nevi, rashes, atopic dermatitis, urticaria, rhytides, pruritis, dysesthesia, eczematous eruptions, eosinophilic dermatosis, reactive neutrophilic dermatosis, pemphigus, pemphigoid, immunobullous dermatosis, fibrohistocytic proliferations of skin, cutaneous lymphomas, cutaneous lupus, and actinic keratosis, does not reasonably provide enablement for cancer generally, preventing pre-cancerous lesions, a pathology characterized by generation of senescent cells and an inflammatory response generally, or a senescence-associated disease or disorder generally. 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.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, "The Federal Circuit has repeatedly held that "the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation." In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)" (emphasis added). The "make and use the full scope of the invention without undue experimentation" language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: "A lack of enablement for the full scope of a claim, however, is a legitimate rejection." The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int'l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
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: (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. Some experimentation is not fatal; the issue is whether the amount of experimentation is "undue"; see In re Vaeck, 20 USPQ2d 1438, 1444.
The treatment of senescence and cancer generally cannot possibly be considered enabled.
By way of background, four cases are of particular relevance to the question of enablement of a method of treating cancers broadly or even generally:
In In re Buting, 57 CCPA 777, 418 F.2d 540, 163 USPQ 689, the claim was drawn to "The method of treating a malignant condition selected from the group consisting of leukemias, sarcomas, adenocarcinomas, lymphosarcomas, melanomas, myelomas, and ascitic tumors" using a small genus of compounds. The Court decided that human testing "limited to one compound and two types of cancer" was not "commensurate with the broad scope of utility asserted and claimed".
In Ex parte Jovanovics, 211 USPQ 907 the claims were drawn to "the treatment of certain specified cancers in humans" by the use of a genus of exactly two compounds, the N-formyl or N-desmethyl derivative of leurosine. Applicants submitted "affidavits, publications and data" for one of the compounds, and a dependent claim drawn to the use of that species was allowed. For the other, no data was presented, applicants said only that the other derivative would be expected to be less effective; claims to the genus were refused.
In Ex parte Busse, et al., 1 USPQ2d 1908, claims were drawn to "A therapeutic method for reducing metastasis and neoplastic growth in a mammal" using a single species. The decision notes that such utility "is no longer considered to be "incredible", but that "the utility in question is sufficiently unusual to justify the examiner's requirement for substantiating evidence. Note also that there is also a dependent claim 5 which specified "wherein metastasis and neoplastic growth is adenocarcinoma, squamous cell carcinoma, melanoma, cell small lung or glioma." The decision notes that "even within the specific group recited in claim 5 some of the individual terms used actually encompass a relatively broad class of specific types of cancer, which specific types are known to respond quite differently to various modes of therapy."
In Ex parte Stevens, 16 USPQ2d 1379 a claim to "A method for therapeutic or prophylactic treatment of cancer in mammalian hosts" was refused because there was "no actual evidence of the effectiveness of the claimed composition and process in achieving that utility."
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: (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. Some experimentation is not fatal; the issue is whether the amount of experimentation is "undue"; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
1) Breadth of claims.
"Cancer" is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. To be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Specifically, the prior art knows that there never has been a compound capable of treating cancers generally. "The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally." (<http://www.uspto.gov/web/offices/pac/dapp/1pecba.htm#7> ENABLEMENT DECISION TREE, Example F, situation 1). 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. Indeed, the existence of such a "silver bullet" is contrary to our present understanding in oncology. 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 environment factors.
Accordingly, there is substantive "reason for one skilled in the art to question the objective truth of the statement of utility or its scope" (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally.
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. Likewise, In re Cortright, 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 applicants' 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."
Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. The skill thus depends on the particular cancer involved. There are some cancers where the chemotherapy skill level is high and there are multiple successful chemotherapeutic treatments. The mechanism in these situations, however, is not necessarily the same as is alleged for these compounds.
One skilled in the art knows that chemotherapy of brain tumors is especially difficult. This is because 1) the blood-brain barrier, which is often intact in parts or all of a brain tumor, will block out many drugs, as it is the purpose of the blood-brain barrier to protect the brain from alien chemicals, and 2) CNS tumors are characterized by marked heterogeneity, which greatly decreases vulnerability to chemotherapy. As a result, many categories of CNS tumors simply have no chemotherapy available. These include, generally, hemangioblastomas, meningiomas, craniopharyngiomas, acoustic neuromas, pituitary adenomas, optic nerve gliomas, glomus jugulare tumors and chordomas, to name just some. With regard to gliomas, GBM is considered untreatable; no effective agents have emerged for the treatment of GBM, despite 20 years of enrolling patients in clinical trials. It is radiation and surgery which are used for low grade gliomas (e.g. pilocytic astrocytoma and diffuse astrocytomas), as no drug has been found effective. There is no drug treatment established as effective for optic nerve gliomas or gangliogliomas. Indeed, very few gliomas of any type are treated with pharmaceuticals; it is one of the categories of cancer that is the least responsive to drugs.
Lymphomas of the stomach are not commonly treated with anti-cancer agents per se, but instead, surgery or radiation and antibiotic therapy (e.g. amoxicillin, metronidazole, bismuth, and omeprazole) are the primary treatments.
Neuroendocrine tumors of the cervix generally do not respond to chemotherapy.
A number of sarcomas, including alveolar soft part sarcoma (ASPS), retroperitoneal sarcoma, most liposarcomas, and the assorted chondrosarcomas, are generally considered not to respond to chemotherapy; no chemotherapeutic agent has been established as effective.
It is important to note that tumors can need to be treated quite differently even though they are tumors of the same organ. For example, the drugs used most often to treat Wilms tumor, the most common malignant tumor of the kidneys in children, are actinomycin D and vincristine. Such drugs are never used with clear cell renal carcinoma, which is treated, although without much success, with immunotherapy using the cytokines interleukin-2 and interferon-alpha. However, such immunotherapy has never been established as effective in non-clear cell RCC forms such as papillary renal cell carcinoma. Despite strenuous efforts over a period of decades, no chemotherapeutic agent has ever been found effective against this cancer. Cancers of the stomach can be lymphomas, GISTs, carcinoid tumors, carcinomas, or soft tissue sarcomas, and for a single agent to be effective against all or even most of these categories would be contrary to what is known in oncology.
The scope of treating inflammation generally is extraordinarily broad. Inflammation is a process which can take place in virtually any part of the body. There is a vast range of forms that it can take, causes for the problem, and biochemical pathways that mediate the inflammatory reaction. It is one of the most pervasive of all body processes. Inflammation is a very general term which encompasses a huge variety of specific processes.
Senescence-associated disorders exhibit a very broad range of effects and origins. For example, some give progressive dementia without other prominent neurological signs, such as Alzheimer's disease, whereas other dementias have such signs, such as Diffuse Lewy Body Disease. Some give muscular wasting without sensory changes, e.g., ALS, and some do have the sensory changes such as Werdnig-Hoffmann. Some are abnormalities of posture, movement or speech, such as Striatonigral degeneration, and other are progressive ataxias, such as OPCA. Some are linked to tau mutations, such as Alzheimer's disease and FTDP-17, and other such as Parkinson's clearly do not. Some affect only vision such as retinitis pigmentosa. Even within those that fall into the same category of effects, there are often striking differences. For example, Alzheimer's disease and Pick's disease both give progressive dementia without other prominent neurological signs. But the characteristic Alzheimer's neurofibrillary tangles are not seen in Pick's Disease, which has straight fibrils, as opposed to the paired helical filaments of Alzheimer's disease. Pick's Disease gives lobal atrophy, not seen in Alzheimer's disease. There are differences in origins, even with what little is known.
2) The nature of the invention and predictability in the art.
With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the "general unpredictability of the field [of] …anti-cancer treatment." In re Application of Hozumi et al., 226 USPQ 353 notes the "fact that the art of cancer chemotherapy is highly unpredictable". More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved," and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
3) State of the Prior Art. The claimed compounds are dihomo-gamma-linolenic acid, gamma-linolenic acid, and inhibitors of D5D. So far as the examiner is aware these compounds have not been successfully used as broad range anticancer or anti-inflammatory agents.
4) Working Examples. Applicants have provided no working examples which are successfully used as broad range anticancer or anti-inflammatory agents. Applicants have, however, demonstrated that DGLA is selectively toxic to senescent IMR-90 fibroblasts (specification, p. 96-97).
5) Skill of those in the art. Many, many mechanisms have been proposed over the decades as methods of treating the assorted cancers generally. Cytotoxic agents could be applied directly to the tumor cells, directly killing them. Immunotherapy involves stimulating the patient's immune system to attack cancer cells generally, either by immunization of the patient, in which case the patient's own immune system is trained to recognize tumor cells as targets, or by the administration of therapeutic antibodies as drugs, so the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies. Another approach would be to increase the amount or activity of the body's tumor suppressor genes, e.g. p53, PTEN, APC and CD95, which can for example activate DNA repair proteins, suppress the Akt/PKB signaling pathway, or initiate apoptosis of cancer cells. The angiogenesis inhibitor strategy was based on cutting off the blood supply that growing tumors need by shutting off the growth of new blood vessels by, for example, suppressing proliferation of endothelial cells or inducing apoptosis of endothelial cells. There is also the cancer stem cell paradigm, which hypothesizes that cancer could be treated generally, either by targeting the cancer stem cells themselves, or by targeting the epithelial-to-mesenchymal transition which supposedly generates the cancer stem cells. Yet another approach is to inhibit one or more of the assorted HSP90 proteins, which will supposedly disrupt the proper folding of signaling proteins that all cancers rely on. Inhibiting telomerase was said to be able to be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Accordingly, there is substantive "reason for one skilled in the art to question the objective truth of the statement of utility or its scope" (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally. Moreover, even if applicants' 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."
The great majority of senescence-associated disorders have no treatment at all, and of those that do, none or virtually none have been treated with such inhibitors as are disclosed here. The great diversity of diseases falling within the "senescence-associated disorder" category means that it is contrary to medical understanding that any agent (let alone a genus of trillions of compounds) could be generally effective against such diseases. The intractability of these disorders is clear evidence that the skill level in this art is low relative to the difficulty of the task. Further, what little success there has been does not point in this direction. Thus, what very few treatments that the massive research effort on Alzheimer's disease has produced are means of providing acetylcholinesterase inhibition, unrelated to the mechanism of action in this case.
6) Scope of the claims. The scope of the claims involves compounds selected from dihomo-gamma-linolenic acid, gamma-linolenic acid, and inhibitors of D5D, and their use as potential treatment to cancers, inflammatory disorders, and senescence-associated disorders. Thus, the scope of claims is very broad.
7) The quantity of experimentation needed. Given the fact that, historically, the development of new pharmaceuticals has been difficult and time consuming, and especially in view of factors 1 and 4 and 6, the quantity of experimentation needed is expected to be great.
MPEP 2164.01(a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." That conclusion is clearly justified here.
Claims 88-98, 101-107, and 112-119 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 DNA damaging or cytotoxic therapy selected from irradiation, chlorambucil, cyclophosphamide, ifosfamide, melphalan, streptozocin, carmustine, lomustine, busulfan, dacarbazine, temozolomide, thiotepa, altretamine, cisplatin, carboplatin, oxalaplatin, 5-fluororacil, 6-mercaptopurine, capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, pemetrexed, pentostatin, thioguanine, anthracyclines such as daunorubicin, doxorubicin, epirubicin, idarubicin , anti-tumor antibiotics such as actinomycin-D, bleomycin, mitomycin-C, topotecan, irinotecan, etoposide, teniposide, mitoxantrone, paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, estramustine, roscovitine, palbociclib, abemaciclib, olaparib, curcumin, valproic acid, azidothymidine, tenofovir, emtricitabine, abacavir, nevirapine, atazanavir, and lopinavir, does not reasonably provide enablement for DNA damaging or cytotoxic therapies generally. 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.
The instant invention is directed toward a method of killing senescent cells in a patient in need thereof, wherein the patient is additionally receiving, has received, or will receive a DNA damaging therapy and/or cytotoxic therapy. The specification does not define that which is intended in the use of a “DNA damaging therapy and/or cytotoxic therapy”. There are hundreds of such therapeutic agents known in the art, many of which are not contemplated by the instant invention, such as abarelix, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anakinra, anastrozole, arsenic trioxide, asparaginase, atra, azacitidine, bevacizumab, bexarotene, bortezomib, calusterone, capecitabine, carboplatin, ccnu, celecoxib, cetuximab, cisplatin, clofarabine, cytarabine, dactinomycin, dalteparin, darbepoetin alfa, dasatinib, daunomycin, decitabine, denileukin, diftitox, dexrazoxane, docetaxel, dromostanolone propionate, eculizumab, elliott’s b solution, epoetin alfa, erlotinib, exemestane, fentanyl citrate, fulvestrant, gefitinib, gemtuzumab ozogamicin, goserelin, histrelin, hydorxyurea, ibritumomab, imatinib mesylate, iressa, irinotecan, lapatinib, lapatinib ditosylate, lenalidomide, letrozole, l-pam, mesna, methoxsalen, mithramycin, mitotane, nandrolone, phenpropionate, nelarabine, nitrogen mustard, nofetumomab, oprelvekin, palifermin, pamidronate, panitumumab, pegademase, pegaspargase, pegfilgrastim, peginterferon alfa-2b, pemetresed disodium, pipbroman, plicamycin, porfimer sodium, procarbazine, rasburicase, sorafenib, sunitinib, talc, tamoxifen, temozolomide, testolactone, thalidomide, tiuxetan, toremifene, tositumomab, trastuzumab, uracil mustard, valrubicin, vm-26, vorinostat, zoledronate, zoledronic acid, etc.
Claims 118-119 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 senolytic agent selected from 25-hydroxycholesterol, a senolytic agent described in U.S. Patent Publication Nos: US 2019/0022090, US 2019/0000846, US 2018/0303828, US 2018/0256568, US 2018/0235957, US 2018/0235956, US 2018/0193458, US 2018/0117038, US 2017/0348307, US 2017/0326136, US 2017/0224680, US 2017/0209435, US 2017/0198253, US 2017/0196858, US 2017/0196857, US 2016/0339019, US 2016/0038576, Nutlin- 3a, Nutlin-3b, RG-7112, RG7388, R05503781, MI-63, MI-126, MI-122, MI-142, MI-147, MI-18, MI-219, MI-220, MI-221, MI-773, 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobe- nzyl)isoindolin- 1-one, RO-2443, RO- 5963, AM-8553, WEHI-539, A-1155463, A-1331852, ABT-263, ABT-199, ABT-737,MK- 2206, CCT128930, JNK-IN-8, sanguinarine chloride, methyl 3-(4-nitrophenyl) propiolate (NPP), AT7867, AZD7762, sunitinib, GDC-0980,BKM120, NQDI-1, R406, erlotinib, CYM7008-00-01, GlcNAc, olaparib, AMG-232, NVP-CGM097, MI-773, CAY10681, CAY10682, Y239-EE, RG-7112, RO-5963, HLI 373, JNJ 26854165, MEL23 MI-773, RG- 7112, JNJ 26854165, AD20187, ABT-263,ABT- 737, WEHI-539, A-1155463, WEHI-539, or MK-2206, does not reasonably provide enablement for senolytic agents generally. 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.
The instant invention is directed toward a method of killing senescent cells in a patient in need thereof, wherein the patient additionally receives a second senolytic agent. The instant specification does not set forth that which is intended in the use of senolytic agent wherein the senolytic agent is a MDM2 inhibitor, CRYAB inhibitor, boronate, BCL-2 inhibitor, benzothiazole-hydrazone compound, aminopyridine compound, benzimidazole compound, tetrahydroquinoline compound, phenoxyl compound, or Akt-specific inhibitor generally. The scope of the claims is incredibly broad such that one of ordinary skill in the art would not be able to ascertain whether a “benzimidazole compound”, for example, is a senolytic agent that can be combined with DGLA, GLA, or a D5D inhibitor, in order to treat a broad array of conditions, without undue experimentation.
Claims 88-98, 101-107, and 112-119 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 88 recites “a delta-5-desaturase inhibitor (D5D inhibitor)”. However, in looking to the specification to construe the scope of a D5D inhibitor, paragraph [0256] refers to compounds 1-354 and those otherwise disclosed in WO2008/089307 and WO2008/089310 as well as compound 326 described in Takagahara et al. Foreign patent applications and non-patent publications cannot be incorporated by reference to provide written description of claimed subject matter. See 37 CFR 1.57 and MPEP 608.01(p). The scope of D5D inhibitor is therefore not adequately described. Correction is required.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 88-98, 101-107, and 112-119 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lammermann et al. (WO 2020/084105 A2; IDS filed 01/19/2024) in view of Climax et al. (WO 2020/079250 A1; IDS filed 09/11/2024) and Wang et al. (Lipids in Health and Disease; IDS filed 09/11/2024).
Lammermann et al. discloses compositions for use in selectively eliminating senescent cells, wherein the composition comprises one or more COX-1 and/or COX-2 inhibitors, including dihomo-gamma-linolenic acid (hereafter, DGLA) (Abstract; p. 6, third paragraph). Lammermann et al. discloses that the compositions can be used for the treatment of senescence-related diseases or conditions, such as age-related diseases and disorders, including atrophy, Alzheimer’s, fibrosis, chronic obstructive pulmonary disease (COPD), and cancer (p. 11, 31-40). Lammermann et al. additionally teaches that the compositions can be administered to subjects in order to reduce toxic side effects from chemotherapy or radiotherapy in a subject receiving the therapy (p. 39-40, bridging paragraph). Lammermann et al. teaches that Bcl-2 inhibitors are known senolytics (p. 2)
Lammermann et al. does not explicitly teach a method of selectively killing senescent cells in a subject comprising administering an effective amount of DGLA, that the subject has a solid tumor, or that the DGLA is administered with a second senolytic agent. These limitations are obvious in view of Climax et al. and Wang et al.
Climax et al. teaches a method of treating inflammatory, fibrotic, and proliferative diseases in a subject comprising administering DGLA (Abstract). Climax et al. discloses that proliferative and inflammatory diseases include cancers and solid tumors (pars. [0026]-[0027], [0089]).
Wang et al. teaches that DGLA has the ability to suppress tumor growth and metastasis by inhibiting motility and invasiveness of human colon cancer cells (p. 4, col. 2). Wang et al. also teaches that DGLA selectively kills tumor cells (p. 5, col. 1).
It would have been prima facie obvious for one of ordinary skill in the art to select DGLA as a COX inhibitor for the elimination of senescent cells in a subject. One would have been motivated to try, with reasonable expectation of success, as DGLA is set forth by Lammermann et al. to be chosen from a list of identified, predictable solutions. One of ordinary skill in the art would additionally be apprised of the antiproliferative effects of DGLA and its potential as an anti-tumor agent and efficacy against cancer cells, making the selection of DGLA advantageous against solid tumors as suggested by Climax et al.
It would have been prima facie obvious for one of ordinary skill in the art to combine DGLA with another senolytic agent, such as a Bcl-2 inhibitor, for eliminating senescent cells. One would have been motivated to do so, with reasonable expectation of success as one would be apprised that the combination of two agents known to have the same function as a senolytic would yield additive effects.
Conclusion
No claims are allowed.
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/M.E.B./Examiner, Art Unit 1624 02/02/2026
/BRENDA L COLEMAN/Primary Examiner, Art Unit 1624