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 1-3, 6-7, 9, 11, 13, 15-18, 37, 41, 46, 50, 52-53 and 56-58 are pending, wherein Claims 56-58 are newly added.
Claims 1-3, 6-7, 9, 11, 13, 15-18, 37, and 53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Claims 1-3, 6-7, 9, 11, 13, 15-18, and 37) and species (Claim 53).
Therefore, Claims 41, 46, 50, 52, and 56-58 are under examination.
Election/Restrictions
Applicant elected Group III (a method for forming an immune response in a subject for treating cancer by administering a PTP1B inhibitor, thereby producing an immune response suitable for treating cancer) and species trodusquemine as the PTP1B inhibitor in the reply filed on 12/4/2023.
Priority
This application is a U.S. national phase of International Application No. PCT/AU2019/050565, filed May 31, 2019, which claims priority to Australian Patent Application No. 2018901979, filed June 1, 2018.
Information Disclosure Statement
The Information Disclosure Statement filed 8/14/2025 has been considered by the Examiner. The submission is 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
Rejection maintained
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 41, 46, 50, 52, and 56-58 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 the use of ptp1b deficiency in forming or producing an immune response in a subject for treatment of breast cancer, does not reasonably provide enablement for
using a ptp1b inhibitor (i.e., not using ptp1b deficiency) to form or produce an immune response in a subject suitable to treat cancer – not even breast cancer, or
forming or producing an immune response in a subject in the treatment of all cancers generally – despite whether the immune response being formed or produced is caused by ptp1b deficiency or by a ptp1b inhibitor.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 41 broadly recites:
“A method for forming an immune response in a subject comprising administering a PTP1B inhibitor to the subject, thereby producing an immune response suitable for the treatment of cancer…”
Thus, the claims are broadly drawn to treating any cancer generally and using ptp1b inhibitors to form or produce an immune response. The claim is structured such that the ptp1b inhibitor is the agent that produces the immune response, i.e., the claim necessitates a causality requirement on the ptp1b inhibitor. This is despite 1) the lack of sufficient evidentiary support for using ptp1b inhibitors to form/produce an immune response suitable for treating cancer and 2) the lack of sufficient evidentiary support for the use of ptp1b deficiency to form/produce an immune response suitable to treat any and all cancers in general.
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:
The nature of the invention and Breadth of claims:
The invention relates to a method of forming/producing an immune response suitable to treat cancer in general by administering a ptp1b inhibitor. The claim encompasses all cancer types, including those not tested and encompasses ptp1b inhibitors, which are not tested in the context of forming/producing an immune response suitable for treating breast cancer, less any cancer in general.
The breadth of the claims is extremely wide: it purports to cover all cancers, including untested cancers, and the use of ptp1b inhibiting agents that are not shown to form an immune response in a subject suitable for treating a cancer.
State and predictability of the art:
Treatment of cancer is unpredictable
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(4), 166. https://doi.org/10.3390/bioengineering9040166) 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) teaches:
“[I]dentical cells in different microenvironments (including tissues, organs, or different 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.
Producing an immune response in a subject with ptp1b inhibitor is unpredictable:
The state of the art of forming/producing an immune response in a subject with a ptp1b inhibitor is unpredictable. In fact, the inhibitory effects on the immune response caused by ptp1b inhibitors would appear to be contrary to the claimed function of forming/producing an immune response in a subject. Recent and earlier literature underscore this concern.
Zasloff et al. (WO 97/44044 – previously cited):
Regarding the ptp1b inhibitor, MSI-1436, as applicant mentioned in the declaration at paragraphs 12-15:
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Thus, Applicant acknowledges that their elected ptp1b inhibitor, i.e., MSI-1436 or trodusquemine, creates the opposite effect being claimed:
“I therefore consider that [a POSA] would consider MSI-1436 to be useful for repression of immune cell activity.” See paragraphs 12-15. Emphasis added in original.
That is, instead of forming or producing an immune response, the compound actually represses the immune response.
Bourebaba et al. (Front. Endocrinol. (Lausanne). 2023 Mar 20; 14:1149610. doi: 10.3389/fendo.2023.1149610. PMID: 37020593; PMCID: PMC10067883) teaches:
“MSI-1436 further reduced the circulating levels of key pro-inflammatory mediators including ILbeta, TNFalpha , and TGF-beta and triggered the Tregs cells activation.” (Abstract.)
Bourebaba along with Applicant’s statements corroborate the teachings of Zasloff, which is that ptp1b inhibition using a ptp1b inhibitor such as MSI-1436 would repress the immune response instead of producing an immune response as claimed.
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 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 sufficient guidance to counteract the known issue regarding forming/producing an immune response in a subject suitable for treating cancer by administering a ptp1b inhibitor to the subject. It does not provide any working examples showing effectiveness of a ptp1b inhibitor in forming/producing an immune response in a subject suitable in treating cancer. The experimental evidence demonstrating the formation of an immune response in a subject suitable for treatment of cancer only in the context of ptp1b deficiency. See figure descriptions at pp. 13-21 and Figures 1-19. That is, the ptp1b gene in the experimental data is genetically missing, not inhibited by pharmaceutical therapy. While Figure 20 at page 21, demonstrates reduction of breast tumor size, it does not support the formation/production of an immune response in a subject suitable for treating breast cancer.
The quantity of experimentation necessary:
Because of the known unpredictability of the art, and in the absence of sufficient experimental evidence of the claimed invention, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used to obtain the claimed effect 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.
Response to argument and declaration
Applicant’s remarks and declaration have been fully considered but are not persuasive. Applicant argues that the claims do not require the PTP1B inhibitor to produce the immune response. However, Applicant’s interpretation is inconsistent with the claim language. As stated in the previous OA, Claim 41 recites:
“…administering a PTP1B inhibitor to the subject, thereby producing an immune response suitable for treating cancer, wherein the subject has received, or will receive, CAR-T cells…”.
The transitional phrase “thereby producing” establishes a causal relationship between the administration of the PTP1B inhibitors and the immune response. The claim is structured such that the ptp1b inhibitor is the agent that produces the immune response, i.e., the claim necessitates a causality requirement on the ptp1b inhibitor. This is despite 1) the lack of sufficient evidentiary support in the as-filed specification for using ptp1b inhibitors to form/produce an immune response suitable for treating cancer.
Applicant’s arguments attempt to broaden the claim beyond its plain meaning. Because the claim expressly requires the immune response to result from the administration of the inhibitor, and the specification does not provide working examples showing that PTP1B inhibitors produce an immune response in subjects.
Relying in-part on Fig. 20, Applicant contends that MSI-1436 allegedly demonstrates forms or produces an immune response suitable for treating any cancer and, specifically, for enhancing CAR-T cell therapy. Applicant asserts the specification provides data in Fig. 20 that pharmacological inhibition of PTP1B recapitulated the effects observed with genetic deletion of the gene encoding PTP1B. However, Fig. 20 does not show formation of an immune response by a PTP1B inhibitor. Fig. 20 reports for breast tumor: 1) tumor growth curves (Panel A), tumor weight (Panel B), mouse body weight (Panel C). The figure does not contain any measurement of immune response, t-cell activation markers, any cytokine measurements, any CAR-T data, or any demonstration that the inhibitor “produces” or “forms” an immune response. Thus, Fig. 20 shows tumor suppression, not immune response formation, less the resulting immune response treating the cancer. Tumor shrinkage does not equal immune response formation. Thus, the claimed invention is not supported by the as-filed disclosure. See MPEP 2164.
Applicant argues that “pharmaceutical inhibition recapitulates genetic deletion” in T cells. However, the specification’s mechanistic evidence (STAT phosphorylation, T-cell activation, cytokine signaling, etc.) is tied to ptpn1 gene deletion, not pharmacological inhibition. There is no mechanistic demonstration in the as-filed specification showing that MSI-1436 produces an immune response. As stated in the rejection “while being enabling for the use of ptp1b deficiency, [the specification], does not reasonably provide enablement for using a ptp1b inhibitor to form or produce an immune response … suitable to treat cancer.” Applicant’s remarks does not overcome this.
Applicant’s reliance on new unpublished data and post-filing data published ~4 years after the effective filing date of the application cannot make the insufficient as-filed specification enabling. See MPEP 2164.05(a). Information published for the first time after the filing date generally cannot be used to show what was known at the time of filing. While a later dated publication cannot supplement an insufficient disclosure in a prior dated application to make it enabling, an applicant can offer the testimony of an expert based on the publication as evidence of the level of skill in the art at the time the application was filed. The post-filing data cannot retroactively add missing teachings (e.g., immune response formation by an inhibitor suitable for treating cancer, cancer treatment other than breast cancer, inhibitor enhancement of CAR-T immune effect in treating cancer, etc.). Applicant attempts to improperly use new post-filing models to generalize across “all cancers”, expanding to, inter alia, melanoma and colorectal, mammary, and ovarian cancers. The post-filing data cannot support and fill in gaps that the earlier specification enables all cancers. See 2164.05(a)
Lastly, the claims are not commensurate in scope with the data proffered to demonstrate unexpected results as required. See 2164.08.
Double Patenting
Maintained rejection
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 41, 46, 50, 52, and 56-58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-9, 11, 16, 22, 49, 50, 52-54, 56, 57, 59, 60, 62, and 64-66 of copending Application No. 17/780,658 (US 2023/0355670 A1) (reference application) in view of Lantz et al. (Obesity (Silver Spring). 2010 Aug;18(8):1516-23. doi: 10.1038/oby.2009.444. Epub 2010 Jan 14. PMID: 20075852). Although the claims at issue are not identical, they are not patentably distinct from each other because the current and reference claims are drawn to inducing an immune response in a subject to treat cancer (e.g., Her-2 positive cancer, a CD 19 positive cancer) by administering a ptp1b inhibitor (e.g., trodusquemine). The reference further claims the administration of a ptpn2 inhibitor, wherein the ptp1b and ptpn2 inhibitors are the same agent. Thus, trodusquemine can serve as the agent that is the ptp1b and ptpn2 inhibitor because trodusquemine is not only a ptp1b inhibitor as mentioned in the reference claims, but it is also a ptpn2 inhibitor as evidenced by Lantz. See the section titled ‘Trodusquemine’s mechanism of action’ at p. 1519 and Figure 4. Each claim set also teach the administration of CAR-T cells.
Claim 50 limits claim 41, wherein the PTP1B inhibitor is administered systemically or by any means that allows the PTP1B inhibitor to enter the circulation. Claim 56 limits claim 41, where the PTP1B inhibitor acts directly on the CAR-T cells. Claim 57 limits claim 41 where the method results in increased expansion and proliferation of the CAR-T cells, compared to a method where the PTP1B inhibitor is not administered. Claim 58 limits claim 41, wherein the method results in increased cell-killing capacity of CAR-T cells, compared to a method where the PTP1B inhibitor is not administered.
A person of ordinary skill in the art (POSA) would have found it obvious to administer the active agents such that they are systemically distributed because the reference method is to illicit an immune response in a subject to treat cancer. The POSA would have sought to administer the active agents systemically to treat lead to treatment of any cancer throughout the body of the subject. Because the CAR-T and ptp1b inhibitor are suggested to be administered in a subject, the POSA would reasonably understand that the agents would come together and that their interaction with each other would illicit an provide a population of leukocytes with enhanced killing capacity as mentioned in the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to arguments
It is acknowledged that Applicant will consider filing a terminal disclaimer once the claims are found otherwise allowable.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622