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 .
Claims 1-17 are pending and under consideration.
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 1-17 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. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Nature of the Invention-The invention relates to treatment of Batten Disease, a lysosomal storage disorder. Batten Disease is associated with numerous different mutations in 14 different CLN genes, CLN1-14.
Breadth of the Claims-The claims are broadly drawn to treatment of a disorder associated with “aberrant” expression of a CLN5 gene or the activity thereof. The claims encompass treatment of any species of subject (animal) using a human, codon-optimized CLN5 gene. It is noted, as well, that the claims do not require any treatment effects and therefore encompass carrying out the method wherein no effect is had. This fails to offer any enabled use.
State of the Art- Mitchell (2023, Front. Genet. 14:1212228, 16 pages .
doi: 10.3389/fgene.2023.1212228) discusses use of an ovine CLN5 codon optimized gene therapy vector to treat Batten disease in sheep and its translation into human trials. Mitchell teaches that many of the disease-causing mutations in humans result in a putative shorter CLN5 protein and some patients will have mutations that preclude any CLN5 protein synthesis. Thus, there is a risk that CLN5−/− individuals, who lack expression CLN5 epitopes, could mount an immune response when they generate full length CLN5 protein (page 14, col. 1). Mitchell also expresses concern about codon optimization of the CLN5 transgene could increase immunogenicity and/or reduce efficacy (page 14, col. 2). Mitchell discusses that while native sequence is preferred, they codon optimized the human sequence for use in human trials because they had done so with the ovine sequence with no adverse effects. Mitchell concludes that there was great translational promise for extending and improving the quality of life in CLN5 patients so long as they have sufficient remaining cortical and cerebellar neurons to benefit, and higher doses are likely to be more effective. This, in 2023, is a statement of great promise; however, it also highlights that the treatment in humans had yet to be carried out and success was not readily predictable with multiple unpredictabilities to face.
Importantly, Jain (2025, Neurology Asia; 30(4) : 1189 – 1201) reviews treatment of Batten disease related to a variety of mutations in the various CLN5 genes and highlights the complexities of the disease and its potential treatment. The clinical presentation of BD is highly variable depending on the type of genetic mutation. BD pathophysiology is a complex play of genetic and cellular mechanisms (page 1189). Jain discusses various AAV serotype vectors and routes of delivery in treatment of Batten Disease. Jain states, “Deliverability varies, effectiveness is different, and side effect profiles are diverse” (1196, para 1). Jain teaches that intracerebroventricular delivery showed varied efficacy in the distribution of genes and a number of obstacles stand between the present stage of discovery and an efficacious, safe application of gene therapy to the BD patient population. Jain also discusses that in general, host immunity to viral vectors could be problematic as neutralizing antibodies against AAV vectors decrease the transduction efficiency and make repeat dosing challenging. This is particularly relevant given that Mitchell hypothesized that high levels of expression would be necessary for treatment in humans (see above).
Additionally, Mitchell (2018, Molecular Therapy Vol. 26 No 10 pages 2366-2378) states, “Unfortunately, a number of workers have assumed that the first ATG in the human CLN5 gene is the start codon, leading to deductions from function and localization studies of uncertain veracity.44, 45 This must be borne in mind when designing vectors expressing the CLN5 protein for human treatments.” (page 2374)
Finally, with regard to extrapolation of data from animal models to treatment of human disease, in a review of therapeutic landscape for Batten disease in Johnson (Nat Rev Neurol. 2019 March ; 15(3): 161–178. doi:10.1038/s41582-019-0138-8) stated "[m]ouse models have been an integral part of Batten disease research. However, neurodevelopmental, neuroanatomical and mechanistic difference between mice and humans present challenges for translation and are apparent in the phenotypic presentation of Batten disease mouse models Specifically, disease presentation varies depending on strain in several Batten disease mouse models, retinal degeneration does not occur or is limited in several models, and most models show delayed or reduced mortality compared with their human counterparts Perhaps as a consequence of these differences, several clinical trials have shown that therapies that showed promise in these mouse models lacked efficacy in patients (although they have generally been safe and well tolerated" (last paragraph on page 6 continues to first two lines on page 7); and "With gene therapy, the field has seen success with combined forebrain and cerebellar delivery of AAV2-PPT1 in Ppt1 mice¹⁴⁷, combined intracranial and intrathecal delivery of AAV9 in Ppt1 mice and AAV1 and AAV2 delivery across several distinct brain regions 150,155" (page 16, bottom of first full paragraph).
Guidance in the Specification-The specification provides guidance with regard to treating Batten disease in sheep using an AAV vector encoding sheep CLN5. The specification does not teach any in vivo methods using the human CLN5 gene in any species, ovine or human.
Quantity of Experimentation-The state of the art (Mitchell and Jain, for example) supports that treatment of Batten disease in sheep using ovine CLN5 gene therapy cannot be necessarily extrapolated to successful treatment of CLN5-associated Batten disease in human. It would require an undue amount of experimentation to adapt the ovine treatment to human and the expectation of success in doing so was low.
Conclusion
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
