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 .
Priority
Examiner acknowledges that, according to the Filing receipt received 06/25/2024, that the instant application 18/349,256 filed 07/10/2023 is a CON of PCT/US2022/070126 filed 01/10/2022, which claims benefit of U.S. provisional application 63/135,370 filed 01/08/2021.
However, the limitations of the instant claims are not adequately supported or enabled in the manner provided by 35 U.S.C. 112(a) or pre-AIA U.S.C. 112, first paragraph by 63/135,370. More specifically, the limitations of HydroxyUreaMethyl Acylfulvene having a negative optical activity and treating a subject with a cancer with high PTGR1 expression and/or a level of expression of PTGR1 that is sensitive to HydroxyUreaMethyl Acylfulvene (let alone SEQ IDs 1-4) are not taught or suggested in their entirety by 63/135,370. Other omissions may also be present. As such, all the instant claims have been awarded the effective filing date of PCT/US2022/070126 filed 01/10/2022.
Specification
The disclosure is objected to because of the following informalities: in paragraph [006], “heterogeneously” should read “heterogeneous”; in paragraph [0029], “that,” should read “that”; in paragraph [0061], "Tble 1" should read "Table 1".
Appropriate correction is required.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it recites language which is implied (i.e., "This application discloses"). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The title of the invention is objected to because “HYDROXYLUREAMETHYL” should read “HYDROXYUREAMETHYL”.
Claim Objections
Claim 7 is objected to because of the following informalities: claim 7 does not end in a period. Appropriate correction is required.
Claim 17 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, claim 17 has not been further treated on the merits.
Drawings
The drawings are objected to because Fig. 5 is illegible due to low resolution (see Drawings filed 07/10/2023). Moreover, a corrected Fig. 5 was not submitted in the substitute drawings filed 05/06/2024 as was requested in the Notice to File Corrected Application Papers mailed 10/05/2023. 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 10-16 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.
Claims 10 and 12 recite “the subject having an increased expression level of PTGR1 gene” and “the subject having an increased expression level of PTGR1 protein” respectively. These limitations lack antecedent basis.
Claims 11 and 13 recite “the PTGR1 gene” and “the PTGR1 protein” respectively. These limitations lack antecedent basis as claim 1 does not contain reference to a PTGR1 gene or protein.
Claims 14-15 recite “the protein for which it encodes”. This limitation lacks antecedent basis, and it is unclear to what “it” refers.
Claim 16 recites “the HydroxyUreaMethyl Acylfulvene sensitivity”. This limitation lacks antecedent basis, as claim 16 depends on claims 1 and 15, but claim 1 does not refer in any way to determining a subject’s sensitivity to HydroxyUreaMethyl Acylfulvene.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 6 depends from itself and therefore does not further limit the subject matter of or include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim 3 is 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 combination therapy with a therapeutic agent selected from the group consisting of temozolomide, bevacizumab, everolimus, carmustine, lomustine, procarbazine, vincristine, irinotecan, cisplatin, carboplatin, paclitaxel, methotrexate, etoposide, vinblastine, bleomycin, actinomycin, cyclophosphamide, and ifosfamide, does not reasonably provide enablement for a combination therapy 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 treating a cancer that has metastasized to the brain or central nervous system comprising administering HydroxyUreaMethyl Acylfulvene which has a negative optical activity. Claim 3 is further directed toward administering the HydroxyUreaMethyl Acylfulvene as a combination therapy. The specification does not define that which is intended in the use of a combination therapy or an additional therapeutic agent. There are hundreds, if not thousands, of therapeutic agents known in the art, many of which are not contemplated or supported by the instant invention. Applicant additionally provides no examples or evidence that such a broad scope of agents could be predictably combined with HydroxyUreaMethyl Acylfulvene for the treatment of a cancer that has metastasized to the brain or central nervous system.
Claims 1-16 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 cancer selected from lung cancer, breast cancer, melanoma, colon cancer, kidney cancer, renal cell carcinoma, mesothelioma, ovarian cancer, pancreatic cancer, sarcoma, leukemia, lymphoma, urothelial cancer, head and neck cancer, osteosarcoma, bladder cancer, glioblastoma, and astrocytoma that has metastasized to the brain or central nervous system, does not reasonably provide enablement for treatment of cancers (that have metastasized to the brain or central nervous system) 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 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.
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 compound is HydroxyUreaMethyl Acylfulvene and its optically negative isomer. So far as the examiner is aware this compound has not been successfully used as a broad range anticancer agent, let alone used against any cancer that has metastasized to the brain or central nervous system.
4) Working Examples. Applicants have provided no working examples which are successfully used as broad range anticancer agents. Applicants have, however, demonstrated that HydroxyUreaMethyl Acylfulvene is expected to be bioavailable in the brain, that brain metastatic tissue from primary breast and colorectal tumors have levels of PTGR1 that are sensitive to HydroxyUreaMethyl Acylfulvene, and that 3D models of patient-derived xenograft brain metastases of primary lung and breast cancers showed dose-dependent sensitivity to HydroxyUreaMethyl Acylfulvene. See specification pages 13-15.
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."
6) Scope of the claims. The scope of the claims involves HydroxyUreaMethyl Acylfulvene and its use as potential treatment to cancers that have metastasized to the brain or central nervous system, thus, the scope of claims is very broad.
7) The quantity of experimentation needed. Given the fact that, historically, the development of new cancer drugs 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.
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) 1-10, 12, and 14-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kulkami et al. (WO 2020081414 A1; published 23 April 2020) in view of Lantern Pharma (PR Newswire; published 15 Dec 2020).
Kulkami et al. discloses a method of treating or managing solid tumor cancer comprising identifying a patient having a solid tumor cancer sensitive to treatment with an illudin having the formula as below (p. 10).
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Kulkami et al. additionally discloses a method of predicting response to treatment in a patient with a solid tumor comprising obtaining a biological sample from the patient, measuring the level of expression of PTGR1 in the biological sample, and comparing the level of expression of PTGR1 in the biological sample to that of a biological sample from a subject not having a solid cancer, wherein an increased level of expression of PTGR1 indicates a likelihood of an effective response to treatment with a compound as below (p. 10-11).
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Kulkami et al. additionally discloses that the illudin compound can be combined with other anti-cancer agents (p. 12). Kulkami et al. also teaches that an improvement in condition or treatment can include about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in measurable disease or condition burden, such as the number of malignant cells or bulk of tumor masses in the subject (p. 5).
Kulkami et al. does not disclose that the cancer is a cancer that has metastasized to the brain or diagnosing the subject as having a brain metastasis, nor does Kulkami et al. disclose that the combination therapy comprises a therapeutic agent selected from temozolomide, bevacizumab, everolimus, carmustine, lomustine, procarbazine, vincristine, irinotecan, cisplatin, carboplatin, paclitaxel, methotrexate, etoposide, vinblastine, bleomycin, actinomycin, cyclophosphamide, and ifosfamide. These limitations are obvious in view of Lantern Pharma.
Lantern Pharma discloses a drug candidate LP-184 (HydroxyUreaMethyl Acylfulvene; see definition in instant specification, par. [0042]) which has been targeted to treat glioblastoma multiforme due to its ability to cross the blood brain barrier (p. 1-2 bridging paragraph, p. 2 fourth paragraph). Lantern Pharma discloses that the ability to cross the blood brain barrier is important for the treatment of central nervous system (CNS) and brain cancers, and that the current standard of care for glioblastomas includes treatments with fractionated ionizing radiation and temozolomide (p. 2, second and third paragraph). Lantern Pharma additionally discloses that LP-184 has also been predicted to target a broader range of CNS cancers including those that have metastasized to the brain (p. 3, second paragraph).
It would be prima facie obvious for one of ordinary skill in the art to identify and treat a cancer in a subject that has metastasized to the brain. One would have been motivated to do so, with reasonable expectation of success, as HydroxyUreaMethyl Acylfulvene can permeate the blood-brain barrier and has demonstrated potency against cancers including glioblastoma and cancers with increased PTGR1 expression. One of ordinary skill in the art would be motivated to treat a cancer that is known in the art to have limited treatment options in standard therapy in order to improve patient outcomes.
It would be prima facie obvious for one of ordinary skill in the art to combine the optically negative isomer of HydroxyUreaMethyl Acylfulvene of Kulkami et al. with fractionated ionizing radiation and/or temozolomide. One would have been motivated to do so, with reasonable expectation of success, as radiation and temozolomide are both standard therapies for the treatment of brain cancers, and one would be apprised that combining agents/treatments known to treat the same disease could yield an improved effect or tumor response.
Claim(s) 11 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kulkami et al. (WO 2020081414 A1; published 23 April 2020) in view of Lantern Pharma (PR Newswire; published 15 Dec 2020) as applied to claims 1-10, 12, and 14-15 above, and further in view of Kelner (US 20220040191 A1; effectively filed 2019).
Kulkami et al. and Lantern Pharma disclose as above, but do not teach that the sequences of the PTGR1 gene or protein of claims 11 and 13, respectively. This limitation is obvious over Kelner.
Kelner teaches nucleic acid sequence SEQ ID NO: 249 and amino acid sequence SEQ ID NO: 250 (see sequence listing), which are identical to the instant SEQ ID NO: 4 and SEQ ID NO: 3. Kelner teaches that these sequences encode PTGR1 and are biomarkers of cancers sensitive to illudofulvene treatment (Abstract, par. [0042]).
It would have been prima facie obvious for one of ordinary skill in the art to use the above sequences in the method of Kulkami et al. One would have been motivated to do so, with reasonable expectation of success, as these biomarkers are known in the art to indicate sensitivity to illudofulvenes which are similar in function to the compound of Kulkami et al.
Claim(s) 1-10, 12, and 14-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over McMorris et al. (WO 200719308 A2; published 2007) in view of Huang (US 20180042921 A1; published 2018) and Knudsen (US 9725769 B1; published 2017).
McMorris et al. discloses the following acylfulvene analog as a preferred embodiment (p. 6).
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McMorris et al. discloses a method of treating or inhibiting cancer by administering a compound, such as above, to a patient, including central nervous system cancers (p. 8, second paragraph) and brain tumors (p. 8, third paragraph). McMorris et al. also teaches that the compounds can be combined with other anti-cancer treatments such as radiation or other chemotherapeutic agents including temozolomide, cisplatin, bevacizumab, carboplatin, carmustine, etc. (p. 4, third paragraph; p. 4-5 bridging paragraph).
McMorris et al. does not disclose that the cancer is a cancer that has metastasized to the brain or diagnosing the subject as having a brain metastasis, nor that the radiation is whole-brain irradiation, fractionated radiotherapy, radiosurgery, or a combination thereof. McMorris et al. does not teach that the effective amount of HydroxyUreaMethyl Acylfulvene results in inhibition of brain metastasis by more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. McMorris does not describe a method of treatment comprising determining the expression of PTGR1. These limitations are obvious in view of Huang and Knudsen.
Huang discloses a method of treating a brain tumor, wherein the brain tumor can be selected from metastatic brain tumor (par. [0050]). Huang additionally teaches that the method further includes subjecting the subject to a radiation therapy, wherein the radiation therapy can be whole-brain irradiation, fractionated radiotherapy, and radiosurgery (par. [0053]).
Knudsen teaches a method for predicting drug responsiveness to an illudin (irofulven) and for treating a patient having cancer comprising detecting a level of expression of one or more biomarkers of sensitivity to irofulven, wherein the level of expression of the biomarker of sensitivity is similar to the level of expression of the biomarker of sensitivity in a cell or tissue known to be sensitive to irofulven or is dissimilar to the level of expression of the biomarkers of sensitivity in a cell known to be resistant to irofulven (col. 3) and administering irofulven to the patient (col. 4). Knudsen teaches that biomarkers of sensitivity include PTGR1 (col. 6, last paragraph).
It would be prima facie obvious for one of ordinary skill in the art to identify and treat a cancer in a subject that has metastasized to the brain. One would have been motivated to do so, with reasonable expectation of success, as HydroxyUreaMethyl Acylfulvene is suggested by McMorris et al. to be useful in treating brain and CNS cancers. Moreover, methods of treating metastatic brain cancers are known in the art, to which HydroxyUreaMethyl Acylfulvene may be applied. One of ordinary skill in the art would be motivated to treat a cancer that is known in the art to have limited treatment options in standard therapy in order to improve patient outcomes.
It would be prima facie obvious for one of ordinary skill in the art to combine the optically negative isomer of HydroxyUreaMethyl Acylfulvene of McMorris et al. with fractionated ionizing radiation and/or temozolomide. One would have been motivated to do so, with reasonable expectation of success, as radiation and temozolomide are both standard therapies for the treatment of brain cancers, and one would be apprised that combining agents/treatments known to treat the same disease could yield an improved effect or tumor response.
It would be prima facie obvious to determine if a cancer that has metastasized to the brain or CNS has elevated PGFR1 expression and to subsequently administer HydroxyUreaMethyl Acylfulvene. One would have been motivated to do so, with reasonable expectation of success, as cancers with elevated PTGR1 are known in the art to be more sensitive to treatment with illudins such as irofulven. One would therefore be apprised that the methods of Knudsen could be applied to HydroxyUreaMethyl Acylfulvene for the treatment of cancer, as HydroxyUreaMethyl Acylfulvene is also an illudin and has a similar function to irofulven.
Claim(s) 11 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over McMorris et al. (WO 200719308 A2; published 2007) in view of Huang (US 20180042921 A1; published 2018) and Knudsen (US 9725769 B1; published 2017) as applied to claims 1-10, 12, and 14-15 above, and further in view of Kelner (US 20220040191 A1; effectively filed 2019).
McMorris et al., Huang, and Knudsen disclose as above, but do not teach that the sequences of the PTGR1 gene or protein of claims 11 and 13, respectively. This limitation is obvious over Kelner.
Kelner teaches nucleic acid sequence SEQ ID NO: 249 and amino acid sequence SEQ ID NO: 250 (see sequence listing), which are identical to the instant SEQ ID NO: 4 and SEQ ID NO: 3. Kelner teaches that these sequences encode PTGR1 and are biomarkers of cancers sensitive to illudofulvene treatment (Abstract, par. [0042]).
It would have been prima facie obvious for one of ordinary skill in the art to use the above sequences in the method of determining PTGR1 expression. One would have been motivated to do so, with reasonable expectation of success, as these biomarkers are known in the art to indicate sensitivity to illudofulvenes which are similar in function to the compound of McMorris et al. and Knudsen.
Claim(s) 1-5, 7-10, 12, and 14-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kulkarni et al. (Oncotarget; published 13 April 2021).
Kulkarni et al. discloses a method of inhibiting the growth of in vitro models of brain metastases originating from primary lung cancers, comprising contacting cell lines with LP-184 (p. 801). Kulkarni et al. discloses that LP-184 has the following structure (Supplementary Figure 1).
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Kulkarni et al. additionally discloses using a 3D model to determine cell line sensitivity to LP-184 (p. 802). Kulkarni et al. teaches that PTGR1 is likely to be a primary causal determinant underlying LP-184 sensitivity prediction, wherein PTGR1 gene expression is significantly correlated with LP-184 sensitivity (p. 799, col. 1). Kulkarni et al. teaches that temozolomide and radiation are used to treat brain tumors and/or metastases (p. 793, col. 1; p. 799, col. 2). Kulkarni et al. also discloses that LP-184 can cross the blood brain barrier and is a promising candidate as a novel treatment for brain metastases (p. 799, col. 1).
While Kulkarni et al. does not specifically teach a method of treating a metastasized brain or CNS tumor in a subject, it would be prima facie obvious for one of ordinary skill in the art to administer LP-184 to a subject in need thereof. One would have been motivated to do so, with reasonable expectation of success, as Kulkarni et al. suggests that LP-184 could be used for patient treatment and demonstrates its in vitro efficacy and its ability to cross the blood brain barrier.
It would be prima facie obvious for one of ordinary skill in the art to combine the optically negative isomer of HydroxyUreaMethyl Acylfulvene of Kulkarni et al. with radiation and/or temozolomide. One would have been motivated to do so, with reasonable expectation of success, as radiation and temozolomide are both standard therapies for the treatment of brain cancers, and one would be apprised that combining agents/treatments known to treat the same disease could yield an improved effect or tumor response.
It would be prima facie obvious for one of ordinary skill in the art to identify and treat a patient with LP-184 based on PGFR1 expression. One would have been motivated to do so, with reasonable expectation of success, as Kulkarni et al. teaches that LP-184 sensitivity and PTGR1 expression are significantly correlated, and Kulkarni et al. discloses known methods of determining PTGR1 expression.
Claim(s) 11 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kulkarni et al. (Oncotarget; published 13 April 2021) as applied to claims 1-5, 7-10, 12, and 14-16 above, and further in view of Kelner (US 20220040191 A1; effectively filed 2019).
Kulkarni et al. disclose as above, but do not teach that the sequences of the PTGR1 gene or protein of claims 11 and 13, respectively. This limitation is obvious over Kelner.
Kelner teaches nucleic acid sequence SEQ ID NO: 249 and amino acid sequence SEQ ID NO: 250 (see sequence listing), which are identical to the instant SEQ ID NO: 4 and SEQ ID NO: 3. Kelner teaches that these sequences encode PTGR1 and are biomarkers of cancers sensitive to illudofulvene treatment (Abstract, par. [0042]).
It would have been prima facie obvious for one of ordinary skill in the art to use the above sequences in the method of determining PTGR1 expression. One would have been motivated to do so, with reasonable expectation of success, as these biomarkers are known in the art to indicate sensitivity to illudofulvenes which are similar in function to the compound of Kulkarni et al.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-5 of U.S. Patent No. 11844772 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The ‘772 patent is directed toward a method of treating an atypical teratoid/rhabdoid tumor comprising administering an effective amount of HydroxyUreaMethyl Acylfulvene with a negative chirality, further comprising administering a second therapeutic agent or radiation.
In looking to the specification to construe the scope of “atypical teratoid/rhabdoid tumor”, the limitation is disclosed to include cancers of the brain that are metastatic (col. 4). Thus, it would be clear to one of ordinary skill in the art that the scope of the invention of the ‘772 patent includes metastatic brain cancers.
Claims 1-15 are provisionally rejected on the ground of non