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
This application is
a continuation of U.S. Application No. 17/500,169, filed on October 13, 2021,
which is a continuation of U.S. Application No. 15/778,796, filed on December 6, 2016, now US Patent No. 11,154,520, issued on October 26, 2021,
which is the U.S. National Stage of International Application No. PCT/US2016/065079, filed on December 6, 2016, published in English,
which claims the benefit of U.S. Provisional Application No. 62/263,880, filed on December 7, 2015.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 1/9/2024 has/have been considered by the Examiner. The submission(s) is/are in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered.
Claim Rejections - 35 USC § 112 – Scope of Enablement
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 16 and 17 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 treating B-cell Acute Lymphocytic Leukemia, does not reasonably provide enablement for liquid cancer 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 practice the invention commensurate in scope with these claims.
The test of enablement requires a determination of whether the disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention. That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Claim 16 and 17 broadly recite:
“a method of treating a liquid cancer, comprising administering 1,3- bis(2-chloroethyl)-1-nitrosourea. melphalan, and hydroxocobalamin (Claim 16), and ascorbic acid (Claim 17)…”
Thus, the claims are broadly drawn to treating any liquid cancer generally by administering 1,3- bis(2-chloroethyl)-1-nitrosourea. hydroxocobalamin, and ascorbic acid. This is despite the lack of sufficient support for treating liquid cancer generally.
The nature of the invention:
The invention relates to a method of treating liquid cancer using 1,3- bis(2-chloroethyl)-1-nitrosourea. hydroxocobalamin, and ascorbic acid. The claim encompasses all liquid cancer types, including those not tested.
Breadth of claim; The amount of direction or guidance provided and the presence or absence of working examples:
The breadth of the claims is extraordinarily wide: it purports to cover all liquid cancers. By contrast, the disclosure teaches only general guidance regarding the identified agents, proposed dose ranges, timing, sequencing, routes of administration and the proposed oxidative-stress/glutathione-reductase mechanism. However, the disclosure contains no actual working example of liquid cancer as the examples are prophetic.
The specification does not provide any working examples showing effectiveness in treating any liquid cancer.
State and predictability of the art:
The state of the art of oncological drug development is recognized as being unpredictable. In vitro cancer cell behavior does not reliably reflect in vivo response, systemic activity, or therapeutic outcome. Recent literature underscores this concern with specificity.
Antunes et al. (Bioengineering (2022), 9, 166) report:
“Cancer models are among the least predictive ones.” (Page 8, Section 3.) “The high failure rate (~90% ± 5) of cancer chemotherapies…is attributed to the highly reductionist in vitro models.” (Page 9.) “[T]here is still a lack of recreation of endless genetic mutations and chaotic molecular involvement during disease progression in in vitro tumor models.” (Page 9.) “In the twenty-first century, another phenomenon of cancer that needs to be taken into serious consideration during modelling is cellular senescence and dormancy in cancer progression and therapy resistance. Senescent cells are a part of the cancerous cellular stroma and are often spared by chemotherapeutic agents. The senescent cells then release cytokines or membrane-bound vesicles, known as secretomes, that induce cancerous growth in the neighborhood. Hence, the senescence-associated tissue microenvironment needs to be considered during modelling.” (Page10.)
These findings emphasize that in vitro assays – despite their availability – fail to replicate essential tumor biology or microenvironments, including heterogeneity and progression patterns.
Tang et al. (Front. Pharmacol. (2024), 15:1466017. doi: 10.3389/fphar.2024.1466017) teach:
Although the application of monolayer cell culture in drug screening is characterized by high throughput, the drug response results obtained in vitro may differ from the in vivo response due to the inability to mimic the complex drug metabolism and drug target environment in vivo. (Page 4.) “The activation of transcription factors in terms of cytokine expression related to the TME was investigated and compared in 3D organoids and conventional 2D cell culture. The enhanced expression of STAT3, NF-kB, and p38 only occurred in the organoids, which significantly promoted the expression of cytokines IL-6, G-CSF and GM-CSF for macrophage recruitment and polarization. The macrophages were localized inside the spheroids, whereas the breast cancer cells were located outside. However, the 2D cell co-culture showed an even distribution of the cancer cells and macrophages. Then the effects of targeting the TAMs drug PF-4136309 was tested on this model. Dead cells were found only in the center of normal culture spheroids, but they were found throughout the spheroids in the PF-4136309 treatment. The organoid model required higher drug dose and longer expose time compared to 2D culture. The phenomenon of activation of transcription factors, cytokine expression, macrophage distribution and drug resistance were masked in 2D culture.” (Page 6.) “[M]any challenges remain before widespread application, including how to ensure standardization and reproducibility of organoid models, how to increase model complexity to more accurately simulate human organs in vitro, and how to address bottlenecks that make it difficult to simulate the vascular system and immune responses. (Page 6.)
Thus, Tang highlight even more nuanced barriers to translation, especially from 2D models and states that even advanced organoid models face real-world constraints.
Chalak et al. (Life (2024), 14, 417. https://doi.org/10.3390/life14030417) teach:
“[C]ell lines may not entirely mirror all the attributes of primary cells in the long term and may yield differing outcomes.” (Page 13.) “When opting for cell lines over primary cells, it is crucial to bear certain considerations in mind. Because cell lines undergo genetic manipulation, their phenotype, inherent functions, and responses to stimuli may undergo alterations. Another critical aspect to consider is the repeated cultivation of cell lines, which can bring about shifts in genotypic and phenotypic features over prolonged periods.” (Page 13.) “Also, a 2011 study of 122 different head and neck cancer cell lines revealed that 37 (30%) were misidentified. Analyses of a variety of tissue culture collections and cells sent to repositories for curation and storage from labs in the United States, Europe, and Asia suggest that at least 15% of cell lines are misidentified or contaminated.” (Page 13).”
These teachings confirm that immortalized cell lines, such as those used to demonstrate H188’s inhibition of 8 cancer cell types, are vulnerable to genetic drift contamination and loss of phenotype. As such, they are not dependable indicators of broader therapeutic efficacy – particularly for untested cancers or untested analogs in the instant genus.
Altea-Manzano et al. (EMBO Reports (2020) 21: e50635. DOI 10.15252/embr.202050635):
“[I] parts of the same tumor) exhibit distinct metabolic programs that lead to a variation in phenotypes.” (Page 1.) “In addition to the widely studied role of genetic alterations driving cancer metabolism, cancer tissue may be affected by…diet…tissue of origin…local microenvironment… tumor heterogeneity.” (Abstract.) “[S]pecific microbe supplementation, and glutamine-deficient diets in a mouse model of myeloma showed that microbe-synthesized glutamine was found to be a critical driver of tumor growth. Further, it stands to say that many of the dietary interventions discussed above will impact the microbial flora and may play a role in cancer initiation, growth, and response to therapy, and thus, the microbiome is a critical consideration when discussing causality of diet effects on cancer.”
These quotes emphasize that tumor metabolism and therapeutic response are not fixed traits but contextually reprogrammed by microenvironmental factors – something that cannot be replicated in vitro. This provides support for the position that inhibition observed in 8 immortalized cancer cell lines cannot be extrapolated to other cancers or formulations without undue experimentation.
Relative skill level:
One of ordinary skill in the art is one with access to reagents, tools and equipment used for diagnosing disease, performing tests and/or administering treatment to individuals. The skilled artisan also has many years of training and experience in either the clinical or laboratory environment or both. Therefore, it is clear that the level of skill of one in the art is high. However, this high level of skill is overcome in view of the limited teachings provided by the specification and the unpredictable state of the art, it would require the skilled artisan undue experimentation to make and use the invention commensurate to the scope of the claims.
The quantity of experimentation necessary:
Because of the known unpredictability of the art, and in the absence of sufficient experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used for treating the multitude of claimed diseases as inferred by the claim and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
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.
Claims 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Glazier et al. (WO 2014/066400) in view of Pierson et al. ("Depletion of Extracellular Cysteine with Hydroxocobalamin and Ascorbate in Experimental Murine Cancer Chemotherapy." Cancer Research, vol. 45; 4727-4731 (1985)). NOTE: each reference recited in IDS.
Claimed invention
Claim 16 is drawn to a method of treating liquid cancers in a subject comprising administering 1,3- bis(2-chloroethyl)-1-nitrosourea. hydroxocobalamin, and ascorbic acid, or pharmaceutically acceptable salts of any of the foregoing.
Claim 17 is drawn to a method of treating liquid cancers in a subject comprising administering 1,3- bis(2-chloroethyl)-1-nitrosourea. melphalan, hydroxocobalamin, and ascorbic acid, or pharmaceutically acceptable salts of any of the foregoing, wherein the melphalan dose is in the range of approximately 20 mg/m² to approximately 200 mg/m².
Prior art
Glazier teaches methods of treating cancer in a subject by overcoming melphalan resistance or hypersensitize cancer cells to melphalan using 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU/carmustine). See abstract; Claim 31. Glazier teaches that oxidative stress may be produced by administering an inhibitor of glutathione reductase together with a redox-cycling agent, and specifically identified BCNU as the glutathione-reductase inhibitor. See Glazier, 00012. The cancer includes metastatic liquid cancers and ALL, AML, CLL, CML and lymphomas. See 00185, 00188. Glazier further teaches that inhibition of glutathione-reductase prevents efficient regeneration of GSH and the treatment with oxidizing agents in the presence of glutathione-reductase inhibition can profoundly depress intracellular GSH levels. See 00364-00366. The melphalan dose is in the range of 20 to 200 mg/m2. See 00553,00555;Claim 1.
While Glazier teaches treatment of liquid cancer with BCNU and melphalan, Glazier does not expressly teach 1) hydroxocobalamin or 2) ascorbic acid.
Pierson teaches in vivo inhibition of P388 lymphocytic leukemia with combined hydroxocobalamin and sodium ascorbate for 10 consecutive days resulted in 70% increase in survival. See abstract; p. 4729, 4730; see also Table 2 on p. 4729. Pierson further states that the treatment oxidizes cysteine and attributes its activity to the thiol-depleting activity of the combined hydroxocobalamin/ascorbate therapy.
A person of ordinary skill in the art (POSA) to include the hydroxocobalamin/ascorbate lymphocytic leukemia treatment taught by Pierson in the liquid cancer BCNU/melphalan-containing treatment of Glazier because Glazier specifically teaches BCNU/melphalan to inhibit regeneration of reduced glutathione and teaches that administration of oxidizing agent further inhibits the cellular thiol/GSH system. Pierson teaches a known therapeutically effective thiol-oxidizing combination of hydroxocobalamin and ascorbate for treatment of lymphocytic leukemia. The POSA would therefore have reason to employ the Pierson’s demonstrated anti-leukemic, thiol-oxidizing combination in Glazier’s BCNU/melphalan treatment to further impair the thiol-dependent protective system of the cancer cells and obtain the known anticancer effect of the Pierson combination with a reasonable expectation of therapeutic benefit.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
Prosecution Insights