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 .
Status
Claims 1-12 are pending. Claims 7-8 and 12 are withdrawn. Therefore, Claims 1-6 and 9-11 are examined.
Election/Restrictions
Applicant’s election without traverse of Group 1, the disease Alzheimer’s, the compound
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and sorafenib in the reply filed on 6/30/2025 is acknowledged.
Claims 7, 8 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (Claims 7-8) and invention (Claim 12), there being no allowable generic or linking claim. Election was made without traverse in the reply filed 6/30/2025.
The elected compound is free of the prior art; however, it is not fully enabled as claimed.
Withdrawn Claim Rejections
Claims 4 and 5 were 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. Applicant’s amendment and corresponding reply pertaining to the newly added limitation have overcome the rejections made of record in the previous Office Action, specifically, the removal offending text.
Claims 1-6 and 9-11 were rejected under 35 U.S.C. 103 as being unpatentable over Dillin et al. (US PG-PUB 2012/0189638) in view of Zhang, Wentao (WO 2008/005538 A2) and Moran et al. (“P4-303: SORAFENIB AS A THERAPEUTIC AGENT AGAINST ALZHEIMER’S DISEASE.” Alzheimer's & Dementia (2008); Volume 4: Alzheimer's Association International Conference on Alzheimer's Disease: Pages T732-T761).
Applicant’s amendment and corresponding reply pertaining to the newly added limitation have overcome the rejections made of record in the previous Office Action, specifically, the removal of the limitation to claim 2 that requires the elected compound only.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6 and 9-11 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 Alzheimer’s disease, does not reasonably provide enablement for treating all other disease encompassed by the claims (e.g., cancer, neurodegenerative diseases generally, etc.) 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 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 1 broadly recites:
“a method for treating a neurodegenerative disorder, Welander distal myopathy, psychiatric illness, or cancer”
Thus, the claims are broadly drawn to treating multiple diseases categories generally by administering a novel compound. This is despite 1) the lack of sufficient support for treating the broad spectrum of diseases claimed.
The nature of the invention:
The invention relates to a method of treating multiple diseases including cancer using the compound claimed. The invention is based on inhibiting Tau or TIA1 and thereby treating many diseases. The claim encompasses many diseases including all neurodegenerative diseases and cancer types.
Breadth of claim:
The breadth of the claims is extraordinarily wide: it purports to cover many categories of diseases including all cancers, all neurodegenerative disorders, all psychiatric illnesses, and Welander distal myopathy using any compound that decreases TIA1-dependent SG formation, and all potential modes of use – whether oral, intravenous, topical, intratumoral, or others. This encompasses at least six distinct disease categories, each with divergent pathophysiological mechanisms, affected cell types, and clinical presentations. This wide breadth of the claims exceeds the scope of the disclosure and weighs heavily against enablement across the full claim scope.
State and predictability of the art:
Cancer is used here as an example of the lack of full enablement. 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 was 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 amount of direction or guidance provided and the presence or absence of working examples:
The specification fails to provide any substantive guidance to counteract to treat all the claimed diseases.
The quantity of experimentation necessary:
Because of the known unpredictability of the art, and in the absence of 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.
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.
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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.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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