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 .
Applicant’s response to restriction requirement and amendment of 11/10/25, are entered.
Claims 2 and 4-14 are pending, the amendment being a restatement of the claims.
Examiner Reassignment
This Application has been reassigned to Examiner Robert M. Kelly, of AU 1638. The Examiner’s information is in the final form paragraphs of the action. Please address the responses accordingly.
Election/Restrictions
Claim 11 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/10/25.
Applicant’s election of the species of SEQ ID NO: 11 for the DOK7 gene (thus not electing protein therapy); CMS with AchR deficiency (thus not electing FCCMS); the AchR deficiency being due to mutation in the CHRNE gene (thus not electing i-iii and v-ix of Claim 5); an AAV vector (claims 7-8); the cholinesterase inhibitor pyridostigmine as an additional agent (Claims 9-10); separate administration (Claim 9); and The DOK7 gene, as required by election of SEQ ID NO: 11, above, in the reply filed on 11/10/25 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
It is noted that applicant elected pridostigmine, as a cholinesterase inhibitor, for Claim 9-10, and thus, the beta-adrenergic receptor agonist is withdrawn, and Claim 14 is therefore withdrawn.
Claim 14 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/10/25.
Claims 2, 4-10, and 12-13 are considered with respect to the elected species, however, if rejections/objections are realized by the examiner during prosecution, the objections/rejections will be made, even though withdrawn, in the interest of compact prosecution.
Specification
The specification is objected to. Figure 1 is described in Example 1, discussing how the AchR are labeled with bungarotoxin in red, and the nerve terminals with synaptophysin, in green. However, the drawings are not in color. The Artisan could not understand what is being conveyed with this statement and the black and white pictures. There is no way to determine that the junctions are enlarged due to DOK7.
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 2, 4-10, and 12-13 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are generic for the prevention of CMS, where the CMS is associated with AChR deficiency, specifically the CHRNE subunit (elected species of Claim 5).
The specification provides antecedent basis for the idea of preventative treatment (e.g., paragraph 1 and page 5, paragraph 3). The idea of this is to prevent, hinder or slow the progression of CMS (e.g., p. 15, paragraph 5). Applicant also teaches that the conditions of the disease may appear different times of life, from childhood, adolescence, to adult years (pp. 4-5, paragraph bridging). Beyond this, there is no teaching on how to identify individuals who do not have CMS, yet can be determined to suffer from CMS in the future, and when to treat such individuals. The examples teach the treatment of the CHRNE KO model mouse, which constitutively has such disorder, as much as mice recapitulate it.
The Art teaches several characteristics of CMS, which often present during childhood, but may not be seen until later years of life (e.g., author unknown, Congenital Myasthenic Syndrome (CMS): Symptoms & Treatment, by the Cleveland Clinic, no volume or issue number, last updated 2/15/24, 11 pages as printed). However, the only way to know who to treat appears to be from the appearance of symptoms of the disorder (Id.).
Thus, the Artisan would not have understood Applicant to have been in possession of prophylaxis.
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 2, 4-7, 9-10, and 12 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
As indicated by non-rejected Claims 8 and 13, the claims are necessarily generic for the aspect of not having a promoter operably linked to express the DOK-7 protein from the gene, thereby treating CMS, as in Claim 1.
The specification fails to describe the system, even in open ended language to provide antecedent basis for the absence of promoter. In fact, it is recognized that the promoter is needed to drive transcription of the transgene (e.g., p. 16, paragraph 2).
The Art also recognizes the essential need of a promoter of some form to drive the transcription of the transgene (Romanova, et al. (2018) “Engineered and Natural Promoters and Chromatin-Modifying Elements for Recombinant Protein Expression in CHO Cells”, Biotechnology Journal, 13: 1700232, 28 pages, e.g., ABSTRACT).
Thus, given the absence of description by Applicant of how to drive the essential expression of the transgene without a promoter, and general knowledge in the Art that a promoter is a required part of transgene expression, the Artisan would not have understood Applicant to have been in possession of the invention as presently claimed.
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 2, 4-10, and 12-13 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 mouse model containing human AChR γ subunit in the AChRε-subunit KO background, as well as human and thus, expressing fetal AChR gamma, through direct administration to the tissue to be treated, does not reasonably provide enablement for (i) the breadth of administration methods, (ii) the breadth of species presently claimed, (iii) the breadth of mutations in CHRNE causing AChR deficiency, nor (iv) the breadth of AChR deficiencies themselves. 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 CMS in the elected CHRNE gene mutation causing AChR deficiency, in the breadth of species, including any mammal. The claims are also broad for the method of delivery and vector utilized to obtain treatments.
The specification teaches DOK7 is a protein involved in the MUSK signal pathway, and functions in the formation and maintenance of the NMJ, citing US PAT APP NO 2009/0158448. DOK7, being one of the major causes of CMS disease. Pages 3-4, paragraph bridging). It also has been shown that administration of DOK7 gene results in enlarged NMJs with increases in muscle strength and life span, citing Arimura (2014) “DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction”, Science, 345(6203): 1505-08 (of record). In Arimura, the therapy is discussed in terms of two mouse models of DOK7 myathenia and Emery-Driefuss, each one increasing the NMJ, and concomitant positive effects on motor activity and lifespan (ABSTRACT), and suggests it may be useful in many disorders of the neuromuscular junction (Conclusion).
The recognizes that DOK7 is a protein that functions with MuSK to phosphorylate the AChR and localize it to the NMJ (e.g., Ohno, et al. (2023) “Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes – A Comprehensive Review”, International Journal of Molecular Sciences, 24: article 3730, 48 pages, see Figure 1 and p. 6-7, paragraph bridging). Thus, it is clear that DOK7 helps to increase the number of AChR channels to the NMJ, thereby making up for decreased function, by way of increased numbers of channels.
Applicant’s examples demonstrate the use of the Cossins’ model of of CHRNE deficiency (Example 1). In this example, mice are treated with IP injection of rAAV to get DOK7 expressed in the muscle, and such produced increased areas of synapse (Figure 1), longer times before grip fatigue (Figure 2), longer and better responses to stimulus (Figure 3), and it works to exert a greater effect than pyridostigmine alone (Figure 4). Example 2-4 are prophetic tests to determine a best delivery form, toxicologic and immune responses, and dose/response curves in tests to determine effectiveness. Further, it is noted that Applicant does not claim specific species of animal to treat, but describes mammals, including several specific mammals (pp. 11-12, paragraph bridging). For administration forms, Applicant describes only IV, IT and IP (e.g., p. 17, paragraph 4). For forms of administration, AAV vectors are the only described for the delivery of the DOK7 gene (e.g., paragraph 1).
The mouse model of Cossins has an important context here, and points out a major problem for the breadth of species encompassed by the claims. To wit, Cossins points out that there exist fetal and adult forms of AChR, the fetal form containing a gamma subunit, while the adult form contains the epsilon (hereinafter “e”) subunit (or in humans CHNRE). In the mouse, when the e subunit is disrupted, the mice are frail and die by 8-14 weeks, which is distinct from humans. While the reasoning is not known for certain, it is believed that fetal specific subunits substitute in the AChR for the non-functional e subunits, allowing humans to survive while mice do not. Thus Cossin’s mouse substitutes the human gamma subunit for the missing e subunit in the null mice, allowing substitution and a condition similar to humans (INTRODUCTION). Thus, from this, and the lack of description from Applicant which mammals are able to use a fetal gamma gene to substitute for the adult mutant e subunit, the Artisan would not know which animals could be treated, save for the Cossins mouse model, and humans.
Moving to the forms of delivery, it has been well known in the field that not any form of administration will allow for proper transfection of the proper tissues with enough vector to produce enough protein for a long enough time to have a therapeutic effect. For example, it is known that any particular vector may transfect any tissue before reaching the tissue of interest, by way of any specific administration. For example many AAVs will target first pass organs, like the liver, lung, kidney, or other tissues, before ever reaching the target muscle cells (e.g., Zincarelli, et al. (2008) “Analysis of AAV Serotypes 1-9 Mediated Gene Expression and Tropism in Mice After Systemic Injection”, Molecular Therapy, 16(6): 1073-80, ABSTRACT). Additionally, AAV vectors are removed in circulation by antibodies in many cases (e.g., Bertin, et al. (2020) “Capsid-specific removal of circulating antibodies to adeno-associated virus vectors”, Scientific Reports, 10: 864, 11 pages, ABSTRACT). Thus, the Artisan would not reasonably predict for any particular form of administration that enough cells in the proper tissue would be transfected to produce enough protein to have an effect. For the record, finally, it is noted that there exist at least 5000 forms of mammal.
Thus, the Artisan would have to experiment to determine which species could be treated through the method in finding out those they have a fetal from of the gamma to substitute for the adult form of the mutant e subunit, and thus be localized to have a beneficial effect. The Artisan would have to experiment to determine which vectors, and administration routes, would lead to transduction of enough tissue to produce enough protein, to have a therapeutic effect. The Artisan would have to determine which subjects are immune to the vector form administered, and thus could not be treated. Such is considered undue experimentation as it is required for the vast majority of embodiments encompassed.
Therefore, the claims are not considered enabled for more than the scope provided in the initial form paragraph.
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