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 .
Priority
Applicant’s priority claim to parent 17/406,723 is acknowledged. Instant application is a DIV of 17/406,723 which claims priority to PRO 63/067,668. The effective filing date for the claims filed 8/13/2024 in the instant applications is 8/19/2020.
Claims status
Applicants preliminary amendment to claims filed 8/13/2024 is acknowledged.
Claims 1-32 is/are cancelled and claims 33-51 is/are newly added and is/are under examination.
Claim Objections
Claims 33, 34, 40, 43, 50 are objected to because of the following informalities: Claims 33, 50 recite “Rett Syndrome-associated gene” while claims 34, 40, 43 recite “Rett-syndrome-associated gene”. Applicant is requested to pick one of these two versions for the sake of consistency. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 33-51 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.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to: 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, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: Claim 33 as currently drafted is directed to treating or delaying the onset of any “MECP2-associated disease” in a subject.
Regarding “treating”, the specification provides the following expansive definition: “refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and/or a prophylactic benefit.” [056] (emphasis added). Thus, treating is broadly interpreted to obtain any beneficial or desirable result, including results that prevent a disease.
Regarding “MECP2-associated disease”, the specification provides the following expansive definition: “"MECP2- associated disease" is a disease which is correlated with, or caused by, genetic changes (for example, one or more deletions, insertions, duplications and/or substitutions) to the mecp2 gene, as compared to the wild type mecp2 gene, and/or alterations to the expression and/or activity of the MECP2 protein, as compared with a wild type MECP2 protein.” [119].
Thus, the claimed method treats, prevents or delays the onset of any disease that is not only caused by any type of MECP2 gene mutation but also any disease that is merely correlated with any type of MECP2 gene mutation. Further, the claimed method treats, prevents or delays the onset of any disease that is not only caused by any type of alteration to (increase or decrease and the like) MECP2 protein expression but also any disease that is merely correlated with any type of alteration to MECP2 protein expression.
Taken together, the claimed method embraces treatment, prevention or delaying of onset of an expansive genus of diseases broadly “associated” with MECP2 gene or protein.
The active step recited in the method is administration of an AAV expression cassette that comprises 5’ and 3’ ITR flanking a minimal human Arc gene promoter (hArcMin) of SEQ ID NO: 12 and any “Rett Syndrome-associated gene”. Although, normally expression cassettes are placed in a vector, in the instant case, the method administers the expression cassette directly. However, the method does not recite any route of administration of the said cassette (intravenous, intradermal, intraparenchymal and the like).
Regarding “Rett Syndrome-associated gene”, the specification provides the following expansive definition: “As used herein, a "Rett Syndrome-associated gene" refers to any gene in a subject with Rett syndrome which can be targeted by gene therapy to alleviate at least one sign or symptom of Rett Syndrome.” [0085].
Of note, there is no requirement that the method results in expression of the claimed “Rett Syndrome-associated gene” in any cell of the subject. Although the cassette comprises a promoter and a transgene, no functional link is required such that the promoter necessarily results in expression of the transgene. This is also evident from claim 34, that recites this functional link. Thus, for claim 33, no such functional link is required.
Thus, the claimed method that embraces treatment, prevention or delaying of onset of an expansive genus of diseases broadly “associated” with MECP2 gene or protein does so by administering an expression cassette by any route of administration wherein the expression cassette comprises 5’ and 3’ ITRs, hArcMin promoter of SEQ ID NO: 12 and any gene that can be targeted in any way to alleviate any sign or symptom of Rett Syndrome.
Consequently, the breadth of claim 33 is expansive.
Claim 34 limits the method of claim 33 wherein a functional link is present between the recited promoter and the expansively recited transgene. Thus, the method of claim 34 embraces treatment, prevention or delaying of onset of an expansive genus of diseases broadly “associated” with MECP2 gene or protein by administering an expression cassette by any route of administration wherein the expression cassette comprises 5’ and 3’ ITRs, hArcMin promoter of SEQ ID NO: 12 that drives the expression of any gene that can be targeted in any way to alleviate any sign or symptom of Rett Syndrome. Consequently, the breadth of claim 34 remains expansive.
Claims 35-39 introduce additional elements to the cassette of claim 34. Each of these elements are transcriptional enhancers. Thus, the method of claims 35-39 embrace treatment, prevention or delaying of onset of an expansive genus of diseases broadly “associated” with MECP2 gene or protein by administering an expression cassette by any route of administration wherein the expression cassette comprises 5’ and 3’ ITRs, recited enhancers, hArcMin promoter of SEQ ID NO: 12 that drives the expression of any gene that can be targeted in any way to alleviate any sign or symptom of Rett Syndrome. Consequently, the breadth of claims 35-39 remains expansive.
Claim 40 limits the Rett Syndrome-associated genes recited in claim 33. Thus, the claimed method embraces treatment, prevention or delaying of onset of an expansive genus of diseases broadly “associated” with MECP2 gene or protein by administering an expression cassette by any route of administration wherein the expression cassette comprises 5’ and 3’ ITRs, hArcMin promoter of SEQ ID NO: 12 and any one of the gene recited in this claim. There is no requirement for expression of these gene. Consequently, the breadth of claim 40 remains expansive.
Claim 41 limits the 5’ and 3’ ITRs of claim 33 to ITRs from any one of the recited AAV genomes. Thus, the claimed method embraces treatment, prevention or delaying of onset of an expansive genus of diseases broadly “associated” with MECP2 gene or protein does so by administering an expression cassette by any route of administration wherein the expression cassette comprises 5’ and 3’ ITRs from any of the recited AAV genomes, hArcMin promoter of SEQ ID NO: 12 and any gene that can be targeted in any way to alleviate any sign or symptom of Rett Syndrome. There is no requirement for expression of these gene. Consequently, the breadth of claim 41 remains expansive.
Claims 42-47 introduce additional elements to the cassette of claim 34. Each of these elements are translational regulators such as UTRs and polyA tails. Thus, the method of claims 42-47 embrace treatment, prevention or delaying of onset of an expansive genus of diseases broadly “associated” with MECP2 gene or protein by administering an expression cassette by any route of administration wherein the expression cassette comprises 5’ and 3’ ITRs, hArcMin promoter of SEQ ID NO: 12 that drives the expression of any gene that can be targeted in any way to alleviate any sign or symptom of Rett Syndrome and recited translational regulators. Consequently, the breadth of claims 42-47 remains expansive.
Claim 48 limits the expression cassette of claim 34 to specifically recited sequences. Each of SEQ ID NO: 3-5 is an expression cassette with AAV2 5’ and 3’ ITRs, hArcMin promoter with hSARE enhancer that drive the expression of BDNF transgene with the difference being different translational regulators: SEQ ID NO: 3 has BDNF short 3’UTR, SEQ ID No: 4 has bGH polyA and SEQ ID NO: 5 has BDNF long 3’ UTR (Figures 1-3). Thus, the method of claims 48 embrace treatment, prevention or delaying of onset of an expansive genus of diseases broadly “associated” with MECP2 gene or protein by administering an expression cassette by any route of administration wherein the expression cassette comprises AAV2 5’ and 3’ ITRs, hArcMin-hSARE promoter-enhancer that drives the expression of BDNF and different translational regulators. Consequently, the breadth of claims 48 is broad.
Claim 49 limits the MECP2-associated disease recited in claim 34. Thus, the claimed method embraces treatment, prevention or delaying of onset of the broadly recited MECP2-associated diseases by administering an expression cassette by any route of administration wherein the expression cassette comprises 5’ and 3’ ITRs, hArcMin promoter of SEQ ID NO: 12 that drives the expression of any gene that can be targeted in any way to alleviate any sign or symptom of Rett Syndrome. Consequently, the breadth of claim 49 remains expansive.
Claim 50 and 51 require the expansively recited Rett Syndrome-associated gene of claim 34 to be expression in neurons, such as active neurons. Since Arc is a neuron-specific promoter, it drives expression in neurons. Thus, the method of claims 50 and 51 embrace treatment, prevention or delaying of onset of an expansive genus of diseases broadly “associated” with MECP2 gene or protein by administering an expression cassette by any route of administration wherein the expression cassette comprises 5’ and 3’ ITRs, hArcMin promoter of SEQ ID NO: 12 that drives the expression of any gene that can be targeted in any way to alleviate any sign or symptom of Rett Syndrome in neurons, such as active neurons. Consequently, the breadth of claim 50 and 51 remains expansive.
(B) The nature of the invention: The invention is in the field of gene therapy for Rett syndrome, a disease caused by mutations in MECP2 gene that results in deficiency of MECP2 protein.
(C) With respect to the state of the prior art: Gene therapy specifically for Rett Syndrome (RTT) using AAV vector based transgene delivery of MECP2 variants is known in the art. Gadalla et al (Molecular Therapy: Methods & Clinical Development Vol. 5 June 2017; IDS 4/8/2026) teach that although use of MECP2 transgene to treat RTT is obvious, gene therapy approaches to achieve this task is complicated by several issue, such as the vector must transduce sufficient neurons while avoiding overexpression of MECP2, which itself is pathologic, and also avoiding vector toxicity (Introduction, para 2). They note that previous attempts using AAV9 did not result in sufficient brain transduction while also suffering from toxic results (Introduction, para 3). Gadalla chose a self-complementary adeno-associated virus (AAV) (scAAV), known for improved transduction, but has reduced packaging capacity to express MECP2 transgene. Gadalla performed systemic administration of their virus at various doses to MECP2 knockout male mouse model (Mecp2-/y) and found that while high-dose was acutely toxic, median doses that improved survival and body-weight had no effect on RTT phenotype (Figure 1). Systemic delivery of the median dose of the virus to Mecp2T158M/y male mice, that harbor a RTT-causing mutation, also had no effect on RTT phenotype (Figure 3). Gadalla attempted several approaches to reduce the acute toxicity of their vectors and also improve brain transduction. Incorporation of a variant of endogenous Mecp2 promoter along with endogenous regulatory elements in the vector along with direct brain injection (intracerebroventricular) was required to observe therapeutic effect on RTT phenotype (Figure 7). Gadalla conclude that viral vectors with improved brain transduction combined with their mecp2 expression cassette that had endogenous regulatory elements would hold translational promise (Conclusion).
Improving on Gadalla’s work, Luoni et al (eLife 2020;9:e52629.) use a instability-
prone Mecp2 (iMecp2) transgene cassette which increases RNA destabilization and inefficient
protein translation of the viral Mecp2 transgene thus limiting supraphysiological Mecp2 protein levels along with intravenous injections of the PHP.eB-iMecp2 virus, a AAV variant that crosses the BBB (Abstract, page 2, para 3). Similar to Gadalla, Luoni also observed that low doses had no effect while severe acute toxicity at high viral vector doses that were required to achieve sufficient brain transduction (Figure 4). Luoni used continuous immune suppression strategy to be able to use their vector system to observe phenotypic benefits (Figure 5).
Of note, each of these studies rely on MECP2 knockout male mouse model (Mecp2-/y) but RTT is well known to be a X-linked disease that occurs in human females. This is critical issue for gene therapy for RTT using MECP2 transgene which needs to be delivered at the correct dose since overexpression is itself pathologic. Sinnett et al (BRAIN 2021: 144; 3005–3019), is a post-filing art, that notes “To further complicate the feasibility of gene therapy, the target human population is primarily females heterozygous for MECP2 mutations, which due to random X-inactivation have cellular mosaicism for MECP2 expression with a roughly equal mixture of dysfunctional cells and wild-type cells. Conceptually, if one delivers a corrected version of MECP2 equally to all cells, there would be the potential to rescue the dysfunctional cells while overexpressing MECP2 in the wild-type cells.” (Introduction, para 5) and “After years of iterative, full-factorial assessments of candidate MECP2 vectors, the field is wrestling with the same dilemma anticipated from MECP2-overexpression studies dating back 16 years. High doses of MECP2-expressing vectors may be harmful; low doses may not be effective.” (Introduction, para 4).
Taken together, although AAV vector based transgene delivery of MECP2 variants for the intended purpose of treating RTT was known in the art, many barriers remained, specifically identifying appropriate vectors with low toxicity while maintaining high neuronal transduction but only achieve appropriate MECP2 expression, not too less but not too high. A gene therapy for RTT using MECP2 transgene remained unpredictable.
Critically, each of these studies are directed to gene therapy of one “MECP2-associated disease”, specifically RTT which is caused by (not merely correlated with) mutations in MECP2 gene that specifically results in reduced expression of MECP2 protein. Furthermore, each of these studies are directed to gene therapy for RTT express MECP2 transgene, not any “Rett Syndrome associated gene”. Finally, each of these studies uses a AAV9 viral vector administered systemically or to the brain, not just an expression cassette as claimed.
Gene therapy approaches for the broadly claimed MECP2-associated disease were not well known, especially using transgene expression. The MECP2-associated diseases, such as recited in claim 49, are highly distinct. A post-filing review of the art by Allison et al (Front. Genet. 15:1332469. 2024) identifies the some MECP2 -associated diseases in Table 1 while include not only the claimed diseases but even more disparate diseases such as Schizophrenia and Multiple Sclerosis. Furthermore, while RTT is a caused by MECP2 gene mutations that result in reduction of MECP2 protein, other MECP2-associated disease such as MECP2 Duplication Syndrome (MDS) is caused by duplication of MECP2 gene resulting in excess of MECP2 protein (page 2, col. 1, para 1).
The art provides no guidance regarding a Rett Syndrome associated gene that would treat other MECP2-associated disease, such as listed in Table 1 of Allison or in claim 49. On the contrary, the teaches treating MDS by antisense oligomers that reduce MECP2 levels (Figure 3 in Sztainberg et al, Nature 528 (7580), 123–126, 2015). Thus, there is no predictability that any Rett Syndrome associated gene, including once listed in claim 40, could treat the wide array of MECP2-associated diseases embraced.
Finally, regarding BDNF, one of the Rett Syndrome associated genes listed in claim 40 and the part of the specific vectors of claim 48.
Using the MECP2 knockout male mouse model (Mecp2-/y), as used above, Chang et al (Neuron 49, 341–348, February 2, 2006; IDS 12/27/2024) show a reduction of BDNF in the brains of these mice (Figure 1). Using a knockin mouse model Chang introduce a conditional BDNF transgene in the genomes of the Mecp2-/y mice which resulted in BDNF overexpression in the cortex of these mice and delay in onset of RTT symptoms (Figure 3, 4). Thus, Chang provides a functional link between genomic BDNF overexpression and RTT phenotype of Mecp2-/y mice. However Chang does not provide any guidance regarding administration of an expression cassette that comprises a BDNF encoding transgene to treat RTT. Chang’s method results in overexpression of BDNF in all cells because of knockin approach. Furthermore, Chang uses a CAG promoter that is well known to drive strong constitutive expression (Generation of Conditional BDNF-Overexpressing Mice). However, the claims are limited to a hArcMin promoter that without the enhancer elements is an extremely weak promoter (see Fig. 1C, 3D Kawasima et al., PNAS, Vol. 106, No. 1, 2009; IDS 12/27/2024). When hArcMin is present with hSARE enhancers, it remains a weak promoter in comparison to constitutive neuronal promoters (Figure 6A from instant specification). Therefore, it remains unpredictable that the claimed expression cassette that comprises hArcMin promoter, alone or in combination with hSARE, would result in sufficient BDNF expression in the brain to allow for a therapeutic outcome, especially when the method comprises administration of just the cassette by any route of administration.
(D) With respect to the level of one of ordinary skill: The level of skill in the art is high with skilled artisans using viral vector delivery and cassette modifications to achieve transgene delivery for therapeutic purposes. However, ordinary artisans do not yet have the skills and the means to titrate transgene expression, such as MECP2 or BDNF, in the brain such as to achieve therapeutic benefit.
(E) With respect to the state of the predictability of the art: As discussed above in section (C), the art remains unpredictable regarding methods of treating any MECP2-associated disease by administering an expression cassette via any route of administration, wherein the expression cassette comprises any RTT associated gene and may or may not result in expression of the RTT associated gene. Even for AAV based systemic or brain delivery of MECP2 transgene for the treatment of RTT, one type of MECP2-associated disease, many challenges remained in the art, specifically achieving sufficient MECP2 expression but not overexpression in the brain. The art provides no predictability that a RTT associated gene, even when expressed in the brain, could treat any MECP2-associated disease, as broadly claimed. Since the claims are limited to hArcMin promoter which is a weak promoter, the art does not provide any predictability regarding the amount of transgene expression of any of the claimed RTT associated gene that would be required for therapeutic outcome such that it could be predicted if hArcMin promoter could drive sufficient transgene expression.
(F), (G) With respect to the amount of direction and working examples provided by the applicant: The applicants have provided examples that are limited to an AAV particles comprising AAV expression cassette comprising hArcMin promoter with hSARE enhancer the drive the expression of reporter transgene (dmScarlet) along with either BDNF long 3’UTR or bGH polyA, tested in mouse primary neurons (Example 4; Figures 5, 6, 8, 12). Although an AAV expression cassette comprising BDNF short 3’UTR was prepared in examples 1-3, this was not tested in the in vitro experiments. The data shows that AAV expression cassette comprising hArcMin promoter with hSARE enhancer result in low expression of the transgene when compared to constitutive neural promoter (Figure 6). Further, hArcMin promoter with hSARE enhancer drive activity-dependent increase in transgene expression however this increase is also significantly lower that constitutive neural promoter, that does not have an activity-dependent increase. Additionally, both AAV expression cassettes with either BDNF long 3’UTR or bGH polyA result in low expression of the reporter gene compared however the cassette comprising the long UTR has slightly higher basal expression (Figure 6B). Example 5 is prophetic, disclosing a cassette comprising BDNF transgene that could be used to test in RTT mouse model.
Applicant provide no example using hArcMin promoter alone.
Applicant provide no example using AAV expression cassette alone could be administered to a subject to achieve therapeutic effect.
Applicant provide no example showing hArcMin promoter, with or without hSARE, could drive any transgene expression, including BDNF to the extent that results in a therapeutic effect in RTT. There is no guidance regarding how much BDNF expression would be required to achieve a therapeutic effect in RTT. There is no guidance regarding other RTT associated genes and there is expression levels to achieve a therapeutic effect in RTT.
Applicant provide no example showing hArcMin promoter, with or without hSARE, could drive any transgene expression, including BDNF to the extent that results in a therapeutic effect in any of the broadly claimed MECP2-associated diseases.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims, the state of the prior art and its high unpredictability, and the limited amount of guidance in the form of varied working examples in the specification.
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).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 33-51, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the invention as claimed would not be enabled by the written disclosure. Therefore, claims 33-51 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to make and use the claimed invention.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632
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