DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 10, 12, 14-16, 21-23, and 31-32 are pending as amended 8/2/23, and are considered herein.
Formalities
The specification is accepted as amended 12/14/22. Please be sure to carry these amendments into any future amendments in the specification.
The drawings of 12/14/22 are accepted.
The IDS of 1/10/24 has been considered herein and is signed off upon (see attached).
Applicant’s priority is noted to go back to the provisional application 60/811,419, and such provisional application is noted to contain support for use of AAVs encoding VEGF as a transgene in treating ALS (e.g., Claim 25).
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 10, 12, 14-16, 21-23, and 31-32 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 mouse models of ALS, does not reasonably provide enablement for the scope of species encompassed. 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/use the invention commensurate in scope with these claims.
The claims are broad for treating ALS in any subject, by administration of an AAV carrying a VEGF transgene, to at least one ventricle of the brain of the subject.
The subjects, as elucidated by Claim 22 include mammals, and specifically rodents, murine species, simian species, and humans.
Applicant’s Example provides support for the treatment of ALS in an SOD1 mouse model (Example 3), where the AAV4 vectors are delivered, intra-ventricularly. The prior Art recognizes intramuscular delivery of lentiviral vectors expressing VEGF, treating the same SOD1 mouse model (Azzouz, et al. (2004) “VEGF Delivery With Retrogradely Transported Lentivector Prolongs Survival in a Mouse ALS Model”, Nature, 429: 413-17, e.g., ABSTRACT; Cited by Applicant in the IDS of 1/10/24, NPL reference 1).
The prior art however, written by and for the Artisan, recognizes that the SOD1 mouse, in which Applicant and the prior art both show positive effects of VEGF delivery, has a poor track record in translating to humans, and by analogy, to other animals. Azzouz for one, without reviewing the problems of translation to humans, or other animals for that matter, concludes that the therapy increases survival in a clinically relevant model of ALS, but concludes that the approach “may have potential as a safe and practical treatment for many of the motor symptoms of human ALS”, inherently recognizing that while it is promising, there exist issues that preclude a conclusion that it is able to treat human ALS. Such relates to the lack of understanding of how VEGF exerts its effect, stating “The mechanism of action of VEGF in this model remains to be characterized, but the data presented here suggests that it may operate by means of a direct effect on motor neurons rather than an indirect consequence of alterations in the vasculature of the spinal cord and brain.” (p. 416, col 2). In fact, it is simply not understood how it works, at this point, and thus, to translate it to other organisms cannot even be determined.
Further, in reviewing treatment trials in the mouse SOD1 model and in human ALS, Benatar (2007) “Lost in translation: Treatment trials in the SOD1 mouse and in humans”, Neurobiology of Disease, 26: 1-13 states:
Therapeutic success in the superoxide dismutase (SOD1) mouse model of amyotrophic lateral sclerosis (ALS) has not translated into effective therapy for human ALS, calling into question the utility of such preclinical data for identifying therapeutic agents that are worthy of further study in humans.
(ABSTRACT).
This is a recognition that the findings in the SOD1 mouse model are not predictive of therapy in other species, particularly humans, at the time of invention. Such may be due to many reasons. For example, Benatar states that the art is full of a small group of studies reporting beneficial results and the non-beneficial results are not published, leading to an overly-optimistic view of the mouse SOD1 model as potentially useful in human clinical trials (p. 6, col. 1, last paragraph), additionally the studies available actually have limited methodological quality, not being randomized, and investigators not being blinded to the treatment groups, and that this leads to lowered quality of results (Id., col. 2, second paragraph). Third, the lack of the studies to consider statistical versus clinical significance, the art being almost devoid of discussion of size of treatment effect and whether it is clinical meaningful, resulting in particular agents unjustifiably being taken to the clinic for trials based solely on statistical significance (p. 7, col. 1, second paragraph). Lastly, Benatar argues that the relevance of the mouse model to human disease is poor, and that SOD1 may more accurately reflect familial ALS more than sporadic ALS, which relates to tests of initiating treatment prior to onset, rather than at the time of onset, demonstrating a lack of understanding of the distinction between sporadic ALS, where it cannot be done before symptom onset (Id., cols. 1-2, paragraph bridging).
Given this disclosure by Applicant and the Art, regarding this mouse model and test results at the time of invention, the Artisan would not reasonably predict therapy in humans, or any other animal, until further studies are conducted to demonstrate the mechanisms, and that enough AAV reaches enough cells, and produces enough protein, for a long enough period of time, to evidence a positive treatment of disease. Such is because of the lack of understanding of the mechanisms, which differs even for ALS forms, and because the model itself was not known to be predictive of therapy in humans (or other animals for that matter).
Such experimentation amounts to that amount which is required to enable the invention on behalf of Applicant, for the vast majority of embodiments, and as such it is considered undue.
Therefore, the claims are only enabled for the SOD1 mouse model.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT M KELLY whose telephone number is (571)272-0729. The examiner can normally be reached M-F: 8a-5p.
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ROBERT M. KELLY
Examiner
Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638