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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission on 12/8/2025 has been entered.
Claims 1, 3-8, 10, 12, 16, 20 and 21 have been amended.
Claims 18 and 19 have been cancelled.
Claim 38 is new.
The rejection of claim 3 under 112(b) is withdrawn in view of Applicant’s amendments.
The 112(a) rejection has been amended, adding the teachings of Pandey et al. and Munnik et al. in view of Applicant’s amendments.
Claims 1, 3-8, 10, 12, 13, 16, 20-22 and 38 are examined in the instant application.
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, 3-8, 10, 12, 13, 16, 20-22 and 38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement for reasons of record in the Non-Final Office Action mailed on 11/7/2022 (and repeated as amended below). The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is ''undue'' (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification, therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention, therefore skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The breadth of the claimed invention encompasses treating any solid tumor with any drug that comprises an inhibitor one or more tumor suppressor signaling networks.
Whereas the nature of the invention is screening a library of drugs in transgenic Drosophila larva expressing one or more orthologs of an oncogene or tumor suppressor(s), a search of the instantly filed specification and the art teaches that the claimed invention is unpredictable.
Working Examples
The specification provides four prophetic examples regarding the development of a genetically modified Drosophila larva and its potential use in screening anti-cancer drugs.
The specification does not teach or guide the skilled artisan how to treat cancer as embraced by the claims.
It is emphasized that the recited method is contingent on the Drosophila larva avatar surviving to pupation after being fed a combination of drugs. There is no treatment of cancer in the Drosophila and that the selection of a therapeutic regimen relies solely on the survival of larva to develop to pupation.
While the specification contemplates using transgenic Drosophila larva expressing an ortholog (oncogene or tumor suppressor) of a subject to screen for candidate anti-cancer drugs, this does not enable a method of treating cancer as embraced by the claims.
Unpredictability of Treatment
An issue of enablement of the claimed invention relies upon targeting of the claimed drug to the breadth of species of solid tumor. There are no teachings in the specification that would teach or suggest that the claimed drug which may be effective on a Drosophila ortholog of a patients oncogene or tumor suppressor used in the method of treatment would be able to treat any solid tumor.
Regarding the challenges of treating cancer the art teaches that “Despite major advances, the current approach to face cancer treatment is still reductionist. Targeting single molecular abnormalities or cancer pathways has achieved good clinical responses that have modestly affected survival in some cancers. However, targeting a single hallmark or pathway with a single drug (“magic bullet”) will not likely lead to cancer cure. We predict that drug combinations against several molecular alterations or cancer hallmarks, in a way that is similar to what we have done with HIV treatment, might be a promising therapeutic strategy to treat cancer in the near future.” (Zugazagoitia et al., 2016, Clin. Therapeutics, Vol. 38, pgs. 1551—1566, see pg. 1564 col. 1 parag. 2 lines 1-12).
Similarly, Lorscheider et al. (2021, Ther. Deliv., Vol. 12(1), pgs. 55-76) teaches that the treatment of cancer has many challenges for the successful treatment of cancer including the drug or combinations of drugs to be used, route of administration, poor solubility and bioavailability (see pgs. 56-68 and Fig. 2, reproduced below).
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It must be emphasized that the claims encompass treating any species of solid tumor using any inhibitor of one or more oncogenes (signaling networks) and/or activator of one or more tumor suppressor signaling networks. While the claims recite that that the drug to treat cancer in a subject is conditioned on the drug being fed to a culture of transgenic Drosophila larva and said drug allows said transgenic larva to survive to pupation, there is no nexus between the drug treatment of the transgenic larva and the treatment of cancer in a patient. The claims require that the drug will allow the transgenic larva to survive to pupation as compared to an untreated larva, which does not survive to pupation. The survival or non-survival of the larva relies upon the activity of an ortholog of an oncogene and/or tumor suppressor, however the art teaches that there are significant limitations to orthologs and their impact on drug screening. For example, Glover et al. (2019, Mol. Biol. Evol., Vol. 36(10), pgs. 2157-2164) teaches that gene conversion, high rates of sequence divergence, and clarity of ortholog definitions all are challenges to successfully using orthologs in animal models (see Abstract, Introduction and pg. 2161 col. 2 parag. 4 bridge pg. 2162 col. 1).
The Method is Contingent on Survival to Pupation
The claims recite that therapeutic regimen will be identified based upon the larva avatar surviving to pupation. However, the art teaches that from larva to pupation in Drosophila is a 4-day process (Manning G., 2008, A Quick and Simple Introduction to Drosophila melanogaster, pages 1-3). While the transgenic Drosophila express one or more orthologs of an oncogene and the claims recite that expression of the ortholog prevents the transgenic larva avatar from surviving to pupation, this skilled artisan would find this unpredictable. There are no teachings in the specification or the art of expressing an ortholog of human oncogene in a Drosophila that would develop cancer in less than four days such that the larva does not develop to pupation. The skilled artisan would find this unpredictable since the art teaches that tumor development in a Drosophila occurs one to two weeks before they die (Gerlach et al., 2020, Genomic instability and cancer: lessons from Drosophila. Open Biol. 10, pgs. 1-17, see pg. 11 Conclusion). It is well known and understood in the art that Drosophila have a lifespan of 40 to 50 days.
Accordingly, the skilled artisan would find that since tumor development takes weeks in a Drosophila and the claims only require the larva to survive for four days till pupation that all of the transgenic Drosophila would survive as embraced by the claims. If all of the larva develop to pupation then the therapeutic regimen selected would not be contingent upon any results observed/screened in the transgenic Drosophila and therapeutic regimen selected would be unpredictable for the treatment of cancer as instantly claimed.
Unpredictability of Animal Models
Further the art teaches the unpredictability of animal cancer models. Specifically, Mak et al. (2014, Am. J. Transl. Res., Vol. 6(2), pgs. 114-118) teaches “Due to practical and ethical concerns associated with human experimentation, animal models have been essential in cancer research. However, the average rate of successful translation from animal models to clinical cancer trials is less than 8%. Animal models are limited in their ability to mimic the extremely complex process of human carcinogenesis, physiology and progression.” (Abstract lines 1-4).
Mak continues to teach that “animal models have been the basic translational model in the preclinical setting in elucidating key biochemical and physiologic processes of cancer onset and propagation in a living organism. Experimental tumors raised in animals, particularly in rodents, constitute the major preclinical tool of evaluating novel diagnostic and therapeutic anticancer drugs screening before clinical testing. The power of the animal models to predict clinical efficacy is a matter of dispute due to weaknesses in faithfully mirroring the extremely complex process of human carcinogenesis. The vast majority of agents that are found to be successful in animal models do not pan out in human trials. Differences in physiology, as well as variations in the homology of molecular targets between mice and humans, may lead to translational limitations. Even though animal models still remain a unique source of in vivo information, other emerging translational alternatives may eventually replace the link between in vitro studies and clinical applications.” (pg. 117 col. 1 last parag.).
The art continues to teach, which respect to D. melanogaster, that “fundamental molecular mechanisms underlying tumorigenesis and metastasis can probably be efficiently probed in D. melanogaster, the fly is not able to model many types of tumors that are common in humans, such as those related to specific tissues (e.g., prostate, ovarian, or breast cancer).” (Pandey et al., 2011, Pharmacological Rev., Vol. 63(2), pgs. 411-436, see pg. 425 col. 1 parag. 3 last sentence).
Regarding the unpredictability of Drosophila avatars for cancer treatment, Munnik et al. (2022, Frontiers in Genetics, Vol. 13 pgs. 1-18) teach that two “avatars” have been created and published by Bangi et al. in 2019 and 2021 (references previously of record and submitted by Applicant) (pg. 12 col. 2 parag. 2 bridge pg. 13, col. 1 parag. 1). Specifically, Munnik teaches that (emphasis added):
“One of the biggest obstacles to overcome, even in multitherapeutic personalized therapy, is the development of drug resistance. Therefore, identifying potential drug resistance could be important in optimizing personalized treatments. Again, personalized Drosophila comes into play as it was found that they could potentially be used to identify biomarkers of drug resistance (Bangi et al., 2014). As the use of Drosophila in multitherapeutic personalized therapy is still in its infancy additional research is needed to fully reach the potential of multitherapeutic personalized therapy in cancer treatment.” (pg. 13 col. 1 parag. 3).
Munnik continues to teach that “Tumors in humans are far more complex than those generated in Drosophila. Cancer fly models, therefore, produce a partial picture of the disease in humans (Willoughby et al., 2013; Richardson et al., 2015; Yadav et al., 2016). The consequence
of such differences may produce pseudo-positive or pseudo-negative findings during drug screening. Drosophila particularly lacks the direct equivalent of the mammalian organs, such as the liver, pancreas, spleen, thymus, kidneys, lungs, and thyroid gland” (pg. 13 col. 2 parag. 1 lines 1-9).
Munnik continues that “The current fly models do not adequately address tumor genetic heterogeneity and evolution observed in human patients. Tumor genetic heterogeneity and evolution play a key role in formation of aggressive and treatment resistant cancers (Pelham
et al., 2020). Whilst there are significant strides made in replicating the genetic architecture of tumors in patients using fly “avatars” and improving treatment, an effort is required to create fly models that will address tumor evolution and heterogeneity in pursuit of improving cancer treatment outcomes.” (pg. 13 col. 2 parag. 2).
Munnik continues to teach that using Drosophila for the treatment of cancer is unpredictable do to (i) differences in immune systems, (ii) physiological and anatomical differences between humans and flied, (iii) route of administration in flies (only oral), the taste of the drug may be undesirable in flies and that drug concentration does not translate to human administration, (iv) and differences in drug metabolism between humans and flies (pg. 13 col. 2 parag. 3 bridge pg. 14 col. 1 parg. 1).
Importantly, Munnik teaches:
“All of these factors, and more, accentuate the use of Drosophila as a screening platform for target discovery, primary small-molecule screening, or post-screening validation to narrow down a large pool of potential drug candidates prior to screening in costly mammalian models.” (pg. 14 col. 1 parag. 2 lines 1-5).
In conclusion, the claimed invention is not enabled for a method of treating cancer as embraced by the claims. The art teaches that there is significant unpredictability regarding the treatment of cancer, using Drosophila models to screen for cancer drugs and unpredictability of orthologs for identifying drugs. Thus the skilled artisan would require an undue amount of experimentation without a predictable degree of success to make and use the invention as claimed.
Response to Arguments
Applicant’s Arguments
Applicants argue in amendment that to build a patient-specific Drosophila model, Bangi I focused its analysis on mutations in recurrently mutated cancer driver genes and genes that regulate cancer-relevant signaling pathways and cellular processes. Bangi I identifies KRAS as an oncogene that functions in the RAS/MAPK signaling pathway and trametinib as an inhibitor of the RAS/MAP signaling pathway. Additionally, Bangi I discloses that bisphosphonates have been previously reported to have antitumor effects both as single agents and in combination with different tyrosine kinase inhibitors. Specifically, Bangi I identifies zoledronate as a bisphosphonate which enhanced the ability of trametinib to inhibit MAPK signaling.
In view of the foregoing, a person of ordinary skill in the art would readily appreciate from Bangi I that: (i) KRAS is an oncogene, (ii) the RAS/MAPK signaling pathway is an oncogene signaling network, and (iii) trametinib is an inhibitor of an oncogene signaling network. Moreover, such a person would understand that zoledronate is an anti-cancer therapy that enhances the ability of trametinib to inhibit the RAS/MAPK signaling pathway. Likewise, a
person of ordinary skill in the art would understand that Bangi I discloses a combination of drugs
comprising "(i) an inhibitor of one or more oncogenes or one or more oncogene signaling
networks and/or an activator of one or more tumor suppressors or tumor suppressor signaling
networks, and (ii) an anti-cancer therapy," as presently claimed.
Applicants continue that Bangi II identifies tofacitinib as an inhibitor of JAK/STAT signaling, a cancer relevant pathway that can be activated downstream of Notch signaling in tumor cells; vorinostat as a histone deacetylase inhibitor that may be particularly relevant for treatment of adenoid cystic carcinoma; and pindolol as a beta blocker with evidence suggesting that inhibition of beta-adrenergic signaling by beta blockers can have anti-tumor effects, including inhibition of tumor cell proliferation, migration, invasion, angiogenesis, and metastases. Bangi II demonstrates that that the 3-drug combination of tofacitinib, vorinostat, and pindolol rescued transgene-mediated lethality in the fly avatar to a greater extent than vorinostat alone, and led to stable disease in a metabolic response in the patient lasting for 12 months.
Since Bangi II identifies NOTCH1 as an oncogene that functions in the NOTCH1
signaling pathway, JAK/STAT signaling as a cancer-relevant pathway that can be activated
downstream of Notch signaling, and tofacitinib as an inhibitor of the JAK/STAT signaling
pathway, a person of ordinary skill in the art would readily appreciate from Bangi II, that (i) NOTCH1 is an oncogene, (ii) the NOTCH1 signaling pathway is an oncogene signaling network, (iii) Notch signaling can activate the JAK/STAT signaling pathway, and (iv) tofacitinib can inhibit JAK/STAT signaling downstream of Notch signaling. Moreover, such a person would understand that vorinostat and pindolol are anti-cancer therapies that enhance the ability of tofacitinib to inhibit signaling downstream of the Notch signaling pathway. Likewise, a person of ordinary skill in the art would understand that Bangi II discloses a combination of drugs comprising "(i) an inhibitor of one or more oncogenes or one or more oncogene signaling networks and/or an activator of one or more tumor suppressors or tumor suppressor signaling networks, and (ii) an anti-cancer therapy," as presently claimed.
In view of the foregoing, Bangi I and Bangi II are commensurate in scope with
the presently claimed invention and, therefore, establish that the as-filed specification fully
enables the presently claimed invention. Accordingly, the rejection of claim 1 (and claims 3-8,
10, 12, 13, 16, and 18-21, which are dependent thereon) for lack of enablement should be
withdrawn.
Examiner’s Response
While Applicant’s arguments have been fully considered they are not found persuasive. As set forth in the amended rejection above, the use of Drosophila models or avatars are unpredictable for the treatment of cancer in humans as embraced by the claims. Importantly, the art teaches that further work is required when using Drosophila as a drug discovery platform for the treatment of cancer, and that when Drosophila are used, then non-human mammalian models are next to be relied upon for drug discovery that may be efficacious for cancer treatment in humans. This is significant, since the specification provides no working examples of how the claimed method is enabled for the treatment of cancer.
While the amended claims recite that an anti-cancer therapy will be administered to the Drosophila, this administration is via feeding, and as Munnik teaches above that the taste of the drug may be an issue of unpredictability regarding testing a drug with Drosophila.
Regarding Applicant arguments with respect to the teachings of Bangi I and II being commensurate in scope with the claimed invention, these are not found persuasive. While the signaling pathways studied and the anti-cancer drugs used in Bangi I and II are related with respect to a potential cancer regimen, this does not enable the claimed invention. The claimed method requires the survival of the transgenic Drosophila larva to develop to pupation, however as set forth above, this would be unpredictable and further is a different scope than the methods taught by Bangi I and II. Bangi II does not teach any pupation at all and Bangi I assessed survival of pupae at two weeks, not the development of larva to pupation, which as taught above is a 4 day period.
As set forth above, the treatment of cancer based upon separate animal models, particularly with Drosophila remains unpredictable and requires more research to enable any treatment of cancer that would rely upon a Drosophila avatar as embraced by the claims. and the breadth of the claimed invention remains non-enabled in view of the teachings in the specification, the art of record and Applicant’s arguments and evidence.
Conclusion
No claims are allowed. The claims are free of the prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID A MONTANARI whose telephone number is (571)272-3108. The examiner can normally be reached M-Tr 8-6.
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/DAVID A MONTANARI/Examiner, Art Unit 1632