DETAILED ACTION
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 preliminary amendment filed on 07/06/2023 is acknowledged. The claims were amended to remove claims 2-111.
Claim 1 is pending and under consideration.
Priority
Acknowledgement is made of Applicant’s claim for priority of international application PCT/US2022/011429 filed on 01/06/2022 which claims benefit of provisional application 63/135,121 filed on 01/08/2021.
Information Disclosure Statement
Receipt of the information disclosure statement(s) on 07/05/2023 and 09/27/2024 are acknowledged. The signed and initialed PTO-1449 form(s) has/have been mailed with this action.
Specification
The disclosure is objected to because of the following informalities:
“RELATES APPLICATIONS” above paragraph [0001] should be amended to recite “RELATED APPLICATIONS”.
“January 8, 2021 entitles …” in paragraph [0001] should be “January 8, 2021 entitled…” or “January 8, 2021 titled…”.
The use of the term(s):
Nikon E800 [0164];
QImaging Retiga 1300 [0164];
Millipore [0165];
GraphPad Prism [0165], [0173];
Beckman [0166];
DC protein assay kit [0166], [0167];
LI-COR biosciences Image Studio [0167];
CK Liqui-UV Test Kit [0169];
Mac OSX [0173];
MATLAB [0178];
Which is a trade name or a mark used in commerce, has been noted in this application. The term(s) should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code:
https://www.licor.com [0167];
Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate correction is required.
Claim Interpretation
The word “inhibiting” in instant claim 1 lacks a definition in the instant specification. However, paragraph(s) [0003] and [0097] contain the word preventing in parenthesis after the word inhibiting. Thus, for the purpose of compact prosecution, “inhibiting” will be interpreted as “preventing”. Wherein the term “prevention” has its plain and ordinary meaning, as stated in paragraph [0112] of the instant specification, including complete or incomplete prevention, or a delay of the onset of, a disease or a sign or symptom of a disease, or change the course of the disease.
Claim Rejections - 35 USC § 112 (Written Description)
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.
Claim 1 is 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 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 fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, Applicant was in possession of
the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
Claim 1 is drawn to a genus of polynucleotide comprising a nucleic acid encoding SERCA polypeptide. The rejected claim thus comprises a genus of polynucleotide(s) encoding SERCA and are defined as belonging to the broad class of polynucleotides and as having the functions of (i) treating skeletal muscular dystrophy.
To satisfy the written description requirement, MPEP §2163 states, in part “… a patent
specification must describe the claimed invention in sufficient detail that one skilled in the art
can reasonably conclude that the inventor had possession of the claimed invention.” Moreover,
the written description requirement for a genus may be satisfied through sufficient description of
a representative number of species by “… disclosure of relevant, identifying characteristics, i.e.,
structure or other physical and/or chemical properties, by functional characteristics coupled with
a known or disclosed correlation between functional and structure, or by a combination of such
identifying characteristics, sufficient to show the applicant was in possession of the claimed
genus.”
The instant specification defines “polynucleotide”, “nucleic acid”, or “nucleic acid molecule” as having their plain and ordinary meaning, for example, polymers comprising DNA or RNA. Nucleic acid molecules can be composed of naturally-occurring nucleotides (such as DNA and RNA) …, (Paragraph [0104]). The instant specification defines “encoding” as having its plain and ordinary meaning and can refer to the property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA (Paragraph [0105]).
The specification envisions the polynucleotide of the instant claim as the following:
In some embodiments, the test agent comprises a polynucleotide. In some embodiments, the polynucleotide encodes a SERCA polypeptide. In some embodiments, the SERCA polypeptide comprises a SERCA2 polypeptide. In some embodiments, the SERCA2 polypeptide comprises a SERCA2 isoform selected from a SERCA2a polypeptide, or a SERCA2c polypeptide. In some embodiments, the SERCA2 polypeptide comprises a SERCA2a polypeptide (Paragraph [0139]).
As well as:
The cis SERCA2a packaging plasmid was modified from a construct published previously. Specifically, a flag tag was fused in-frame to the C terminus of the human SERCA2a cDNA. SERCA2a expression was regulated by the cytomegalovirus promoter, a hybrid intron, and the bovine growth hormone polyadenylation signal. The AAV9 vector was produced, purified, and titrated according to our published protocol. A total of 6 X 1012 vg particles/mouse of the AAV9 SERCA2a vector were injected via the tail vein to conscious 3-month-old mdx mice (Paragraph [0163]).
The specification contains the following four working examples encompass the polynucleotide described above:
Example 1 (corresponding to all sub panels of Figure 1-8 in the drawings) adequately describes human SERCA2a use in mice by injection of AAV9, wherein SERCA2a is operable linked to a CMV promoter (see paragraph [0147]).
Example 2 describes utilizing in vitro techniques of infecting DMD-hvCTS with AAV1.SERCA2a and monitoring abnormalities (see paragraph [0174]).
Example 3 describes phase-2 clinical trials with AAV1/SERCA2a in subjects with cardiomyopathy secondary to DMD (see paragraph [0179]).
Example 4 describes evaluating whether AAV1.SERCA2a could treat, reverse or ameliorate some or all of the cardiac abnormalities in the porcine model for DMD (see paragraph [0207]).
Other than SERCA2a, the instant specification fails to describe the other SERCA sequences that can treat skeletal muscular dystrophy in a subject. Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claim with regard to structure and function, the examples are only representative of human SERCA2a. The results are not necessarily predictive of all polynucleotides comprising a nucleic acid encoding a SERCA polypeptide. Thus, it is impossible for one to extrapolate from the one disclosed polynucleotide encoding SERCA2a described herein that the genus of polynucleotides claimed in instant claim 1 would necessarily meet the structural/functional characteristics of the rejected claim.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe that all SERCA isoforms are capable of treating skeletal muscular dystrophy.
Periasamy et al (Muscle Nerve, Vol 35, Pages 430-442, 2007; Cited as NPL #56 on IDS filed 09/07/2024) discloses:
“The SERCA isoform diversity is dramatically enhanced by alternative splicing of the transcripts, occurring mainly at the COOH-terminal. At present, more than 10 different SERCA isoforms have been detected at the protein level. These isoforms exhibit both tissue and developmental specificity, suggesting that they contribute to unique physiological properties of the tissue in which they are expressed.” (Abstract and See Table 1).
More specifically, Periasamy et al discloses that in vertebrates, three distinct genes encode SERCA 1, 2, and 3. SERCA1 is expressed in fast-twitch skeletal muscle and it is alternatively spliced to encode SERCA1a (994 amino acids, adult) and 1b (1011 amino acids, fetal). SERCA2 encodes SERCA2a (997 amino acids) and expressed predominantly in cardiac and slow-twitch skeletal muscle. SERCA2b (1042 amino acids) is expressed in all tissues at low levels including muscle and nonmuscle cells. SERCA2c (999 amino acids) has been reported in cardiac muscle. SERCA3 isoforms are expressed in several nonmuscle tissues but appear to be a minor form in muscle. SERCA3 is known to encode six isoforms 3a-3f at the mRNA level, expressed in multiple tissue and cell types. At the protein level there are only data for 3a, b, and c isoforms, expressed at high levels in the hematopoietic cell lineages, platelets, epithelial cells, fibroblasts, and endothelial cells (Page 431 Column 2 Paragraph 2 to Page 432 Column 1 Paragraph 1).
Goonasekera et al (J Clin Invest, Vol 121, Pages 1044-1052, 2011;Cited as NPL #32 on IDS filed 09/27/2024) does discloses that skeletal muscle-specific overexpression of SERCA1 improves dystrophic phenotypes but fails to disclose that administration of a polynucleotide comprised of a nucleic acid encoding a SERCA1 polypeptide would work in a similar fashion:
“Here we have shown that the dystrophic phenotype observed in δ-sarcoglycan–null (Sgcd–/–) mice and dystrophin mutant mdx mice is dramatically improved by skeletal muscle–specific overexpression of sarcoplasmic reticulum Ca2+ ATPase 1 (SERCA1). Rates of myofiber central nucleation, tissue fibrosis, and serum creatine kinase levels were dramatically reduced in Sgcd–/– and mdx mice with the SERCA1 transgene, which also rescued the loss of exercise capacity in Sgcd–/– mice. Adeno-associated virus–SERCA2a (AAV-SERCA2a) gene therapy in the gastrocnemius muscle of Sgcd–/– mice mitigated dystrophic disease.” (Abstract).
However, the instant specification discloses at paragraph [0158] that, “In addition, SERCA2a was used instead of SERCA1 because the latter does not express in the heart of wild-type animals. SERCA2a is a better therapeutic target because it can be used to treat both skeletal and cardiac muscle.”
Therefore, merely stating that the treatment of a skeletal muscular dystrophy comprising administering a polynucleotide comprising a nucleic acid encoding a SERCA polypeptide, without sufficient detail relating to the nine other species of SERCA isoforms under the genus SERCA, especially regarding the SERCA3 isoforms, which are essentially free from the art of treating skeletal muscular dystrophy, does not allow the skilled artisan to reasonable conclude that the Applicants were in possession of the claimed invention for claim 1.
Claim Rejections - 35 USC § 112 (Enablement)
Claim 1 is 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 A method of treating or ameliorating cardiomyopathy in a subject with Duchenne muscular dystrophy (DMD), comprising: administering an adeno-associated viral vector (AAV) comprising a polynucleotide comprising a nucleic acid encoding a sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) polypeptide to the subject, does not reasonably provide enablement for (1) inhibiting (synonymous with preventing) a skeletal muscular dystrophy; (2) any and all skeletal muscular dystrophies; (3) any and all delivery formulations; or (4) any and all SERCA polypeptides encoded by a nucleic acid from a polynucleotide.
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 or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claim, 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 the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claim, with the most relevant factors discussed below.
Nature of the invention:
Claim 1 is drawn to a method of treating, inhibiting (preventing) or ameliorating a skeletal muscular dystrophy in a subject, comprising: administering a polynucleotide comprising a nucleic acid encoding a sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) polypeptide to the subject.
Breadth of the claims:
The broadest reasonable interpretation of claim 1 is that the claim encompasses (1/2) treating, inhibiting (preventing) or ameliorating any skeletal muscular dystrophy (which include Duchenne, Becker, Limb-Girdle, Facioscapulohumeral, Myotonic, Congenital, Distal, Oculopharyngeal, and Emery-Dreifuss); (3) through any delivery formulation (which include: viral vectors such as AAV, lentivirus or retrovirus, or non-viral such as lipid nanoparticles, liposomes, polymers, or gymnosis); and (4) a polynucleotide comprising a nucleic acid encoding a SERCA polypeptide (which include: SERCA1a, SERCA1b, SERCA2a, SERCA2b, SERCA2c, SERCA3a, SERCA3b, SERCA3c, SERCA3d, SERCA3e, or SERCA3f). Thus, the complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples:
(1) The instant specification provides guidance on treating or ameliorating cardiomyopathy, “In some embodiments, the treating, inhibiting or ameliorating reduces myocardial remodeling and/or fibrosis in the subject compared to a subject not administered the polynucleotide.”, (Paragraph [0008]). “Some embodiments include methods of treating, inhibiting or ameliorating a skeletal muscular dystrophy, such as DMD in a subject, such as a human male subject, prior to an onset of muscle tissue damage predicted to result from the skeletal muscular dystrophy, the method comprising intravenous administration (administration by intracoronary infusion [0132]) of a single dose comprising about 3 X 1013 vg AAV1 vector comprising a polynucleotide comprising a CMV promoter operably linked to a nucleic acid encoding a SERCA2a polypeptide.”, (Paragraph [0131]). Other parts of the instant specification highlight, “SERCA2a therapy significantly enhanced grip force and treadmill performance, completely prevented myocardial fibrosis, and normalized electrocardiograms (ECGs).”, (Paragraph [0099]).
Working example 1 describes how systemic SERCA2a therapy in young mdx mice prevented dilated cardiomyopathy in terminal age mdx mice, “Remarkably, systemic SERCA2a therapy completely prevented myocardial fibrosis and normalized cardiac electrophysiology (FIGs3A-3E). Major hemodynamic parameters at the systole and diastole were restored to the wild-type level (FIGs3A-3E; TABLE 1). These results indicated that mechanism-based gene therapy with a disease modifier (such as using SERCA2a to restore cytosolic calcium homeostasis in DMD).”, (Paragraphs [0151] and [0153]). Additionally, “Significant improvement was observed in overall body muscle function (forearm grip force and treadmill performance), cardiac electrophysiology (ECG), and heart contractility (hemodynamics). Moreover, SERCA2a therapy effectively prevented myocardial remodeling and fibrosis, although a reduction in skeletal muscle pathology was not observed. Although further studies are needed to clarify this discrepancy, it may likely due to the timing of AAV injection.”, (Paragraph [0159]). Working example 2 was performed in iPSC cells taken from patients with DMD. Working example 3 is using SERCA2a aav1 in subjects with cardiomyopathy secondary to DMD. Working example 4 was performed in a porcine model for DMD in which porcine subjects lack exon 52 of DMD gene. Subjects were evaluated on whether AAV1.SERCA2a could treat, reverse, or ameliorate some or all of the cardiac abnormalities in the porcine model of DMD (Paragraph [0207]).
The term preventing implies prophylactic efficacy, i.e., how effective a preventative treatment is at stopping a disease or condition before it starts. Since skeletal muscular dystrophies are genetic, they cannot be prevented at this moment in time given the state-of-the-art. The instant specification envisions treating or ameliorating myocardial remodeling and/or fibrosis; however, it does not disclose preventing skeletal muscular dystrophy. Working example 1 explicitly details “preventing” dilated cardiomyopathy/ myocardial fibrosis in young mdx mice, however, DMD itself was not prevented. Working example 2 was performed in iPSC cells taken from patients who have DMD, thus, DMD was not prevented. Working example 3 uses the SERCA2a AAV1 in subjects with “cardiomyopathy secondary to DMD” (Paragraph [0179]), thus, DMD was not prevented. Lastly, in working example 4, subjects were evaluated on whether AAV1.SERCA2a could treat, reverse, or ameliorate some or all of the cardiac abnormalities in the porcine model of DMD (Paragraph [0207]), thus, it was the treatment/reversal/amelioration of the cardiac abnormalities and not DMD itself. Therefore, the instant specification only provides guidance treating or ameliorating cardiomyopathy in DMD for the purpose of enablement.
(2) The instant specification provides guidance on the skeletal muscular dystrophy, “In some embodiments, the muscular dystrophy comprises Duchenne muscular dystrophy (DMD) or Becker's muscular dystrophy (BMD).”, (paragraph [0003]). “In some embodiments, skeletal muscles comprise the muscular dystrophy. For example, non-cardiac muscles comprise the muscular dystrophy. In some embodiments, the muscular dystrophy comprises Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, or myotonic dystrophy.”, (paragraph [0118]). However, working example 1 is performed in a DMD mouse model. Working example 2 is performed in human ventricular cardiac tissue model of cardiomyocytes differentiated from DMD derived iPSCs. Working example 3 a clinical trial to treat DMD. Working example 4 is an in vivo study in a porcine model for DMD. While the instant specification envisions the use of the method in any and all skeletal muscular dystrophy, it only provides exceptional guidance on models of DMD and its related cardiomyopathy for the purpose of enablement.
(3) The instant specification provides guidance on the delivery formulations wherein, “In some embodiments, the polynucleotide comprises a vector. In some embodiments, the vector is selected from an adeno-associated virus (AAV) vector, a lentivirus vector, and a retrovirus vector. In some embodiments, the vector comprises an AAV vector. In some embodiments, the AAV vector encodes an AAV or fragment thereof having a serotype selected from any one of AAV serotypes 1-12. In some embodiments, the AAV vector encodes an AAV or fragment thereof having a serotype selected from an AAV serotype-1 (AAV1), and an AAV serotype-9 (AAV9).”, (paragraph [0010]).
“Some embodiments of the methods and compositions provided herein include systemic delivery of SERCA2a with AAV to improve calcium recycling and provide long-lasting benefits in DMD. In some embodiments, the delivery is a single dose. As disclosed herein, an AAV9 human SERCA2a vector (6 X 1012 viral genome particles/mouse) was injected intravenously to 3-month-old mdx mice, a DMD model.”, (see paragraph [0099]).
“Adeno-associated virus serotype-9 (AAV9) is a vector for body-wide skeletal muscle and heart gene delivery. Systemic AAV9 therapy has yielded success in treating neuromuscular diseases in human patients. Two clinical trials have also been initiated to test systemic AAV9 gene therapy in DMD patients. Some embodiments disclosed herein include a single intravenous injection of a human SERCA2a AAV9 vector for lifelong disease rescue in the mdx model of DMD. Mice were treated at 3 months of age and followed until the end of their life expectancy. AAV9 injection resulted in body-wide muscle expression of human SERCA2a and significant enhancement of SR calcium uptake. Importantly, treatment significantly improved whole-body muscle performance and ameliorated fatal dilated cardiomyopathy. Some embodiments disclosed herein include development of dystrophin-independent gene therapy for DMD by the administration of a SERCA2a AAV vector (e.g., AAV9).”, (paragraph [0102]).
Working example 1 uses an AAV9 vector to package the SERCA2a gene (paragraph [0147]). Working example 2 uses AAV1 carrying the CMV promoter driving the cardiac isoform of SERCA2a (paragraph [0177]). Working example 3 uses AAV1 expressing the transgene for SERCA2a isoform (paragraph [0180]). Working example 4 uses AAV1.SERCA2a on Porcine subjects lacking exon 52 of the DMD gene (paragraph [0207]). While the instant specification envisions the use of an AAV, lentivirus vector, or a retrovirus, it only provides exceptional guidance on the use of AAV9 and AAV1 for the purpose of enablement.
(4) The instant specification provides guidance on the polynucleotide, wherein, “In some embodiments, the test agent comprises a polynucleotide. In some embodiments, the polynucleotide encodes a SERCA polypeptide. In some embodiments, the SERCA polypeptide comprises a SERCA2 polypeptide. In some embodiments, the SERCA2 polypeptide comprises a SERCA2 isoform selected from a SERCA2a polypeptide, or a SERCA2c polypeptide. In some embodiments, the SERCA2 polypeptide comprises a SERCA2a polypeptide.”, (Paragraph [0139]).
“The cis SERCA2a packaging plasmid was modified from a construct published previously. Specifically, a flag tag was fused in-frame to the C terminus of the human SERCA2a cDNA. SERCA2a expression was regulated by the cytomegalovirus promoter, a hybrid intron, and the bovine growth hormone polyadenylation signal. The AAV9 vector was produced, purified, and titrated according to our published protocol. A total of 6 X 1012 vg particles/mouse of the AAV9 SERCA2a vector were injected via the tail vein to conscious 3-month-old mdx mice., (Paragraph [0163]).
Working example 1 (corresponding to all sub panels of Figure 1-8 in the drawings) adequately describes human SERCA2a use in mice by injection of AAV9, wherein SERCA2a is operable linked to a CMV promoter (paragraph [0147]). Working example 2 describes utilizing in vitro techniques of infecting DMD-hvCTS with AAV1.SERCA2a and monitoring abnormalities (paragraph [0174]). Working example 3 describes phase-2 clinical trials with AAV1/SERCA2a in subjects with cardiomyopathy secondary to DMD (paragraph [0179]). Working example 4 describes evaluating whether AAV1.SERCA2a could treat, reverse or ameliorate some or all of the cardiac abnormalities in the porcine model for DMD (paragraph [0207]). While the instant specification envisions the use of all SERCA isoforms, it only provides exceptional guidance on the use SERCA2a for the purpose of enablement.
Predictability and state of the art:
Turning to the state of the art on guidance on treatment of skeletal muscular dystrophies. Rawls et al (Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies, Biomolecules, 2023, Vol 13, Issue 1536, pages 1-31) discloses that, “Muscular dystrophies are a heterogenous group of genetic muscle-wasting disorders that are subdivided based on the region of the body impacted by muscle weakness as well as the functional activity of the underlying genetic mutation… With the progression of these disorders, many patients suffer cardiomyopathies with fibrosis of cardiac tissue.”, (Abstract). More specifically, “To date, mutations in 57 genes have been identified that cause nine specific classes of muscular dystrophy.”, (Page 1, Introduction, Paragraph 1). Rawls et al continues to disclose that, “There are no curative treatments for any dystrophies currently, but new AAV and base editing approaches to provide the missing proteins or fix the genetic lesion provide hope… Therefore, understanding the mechanisms underlying inflammation and other pathogenic processes will aid in identifying therapeutic approaches that can ameliorate the progression of these diseases.” (Page 1, Introduction, Paragraph 2). Rawls et al discloses that, “The level of cytosolic Ca2+ is affected by channels that pump Ca2+ back into organelles, including the SR and mitochondria. Perhaps the most important among these is the SR Ca2+ ATPase family (SERCA1 and 2), which can remove >70% of the Ca2+ from the muscle cytosol during muscle fiber relaxation.”, (Page 6, paragraph 1). Lastly, “The abnormally high intracellular Ca2+ concentrations and oxidative stress in the muscle of DMD patients lead to calcium overload of the mitochondria and the opening of the mitochondrial permeability transition pore (MPTP)... MPTP-dependent cell death contributes to the inflammation and pathophysiology of DMD and other MDs. Excess Ca2+ in the mitochondria is released when the MPTP opens, further disrupting calcium homeostasis.”, (Page 6, paragraph 3).
With muscular dystrophies being a heterogenous group of genetic disorders characterized by mutations in 57 genes subdivided into different regions of the body, a method to treat or ameliorate, any and all of the skeletal muscular dystrophies is not enabled by the current state of the art. However, treating or ameliorating the pathology of skeletal muscular dystrophies, namely cardiomyopathy, is enabled. Rawls et al discusses that AAVs are being used for Emery-Dreifuss (EDMD) (page 9, paragraph 2) and limb-girdle (LGMD) (page 12, table 3), thus AAV is enabled as the delivery vehicle of a polynucleotide. Lastly, Rawls et al discusses how both SERCA1 and 2 can remove >70% of Ca2+ from muscle cytosol. Both SERCA1 and SERCA2 are enabled, however, the instant specification discloses at paragraph [0158] that, “In addition, SERCA2a was used instead of SERCA1 because the latter does not express in the heart of wild-type animals. SERCA2a is a better therapeutic target because it can be used to treat both skeletal and cardiac muscle.” If SERCA1 is not expressed in the heart of wild-type animals, and SERCA2a is the better therapeutic target, then SERCA2, specifically SERCA2a is only enabled for a method of treating or ameliorating cardiomyopathy in a subject with Duchenne muscular dystrophy (DMD), comprising: administering an adeno-associated viral vector (AAV) comprising a polynucleotide comprising a nucleic acid encoding a sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) polypeptide to the subject.
Amount of experimentation necessary:
Given the lack of predictability in the prior art and lack of guidance provided by the specification with respect to (1) preventing genetic diseases, namely skeletal muscular dystrophies; (2) any and all skeletal muscular dystrophies; (3) any and all delivery formulations; or (4) any and all SERCA polypeptides encoded by a nucleic acid from a polynucleotide, further experimentation is required. Considering that the additional experiments would require de novo experimentation of any and all skeletal muscular dystrophies, along with lentiviral, retroviral, and non-viral delivery formulations, and the nine other SERCA isoforms (potentially 630 different combinations to test, e.g., 9 dystrophies, 7 delivery formulations, and 10 SERCA isoforms) without a guarantee of success, and further considering that any positive results (e.g., successful treatment of all skeletal muscular dystrophies in a subject) with any and all SERCA isoforms with all of the different formulations, would amount to a significant advancement in the state of the art, the additional experimentation required is undue.
Furthermore, in In re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991),
the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was
appropriate given the relatively incomplete understanding in the biotechnological field involved,
and the lack of a reasonable correlation between the narrow disclosure in the specification and
the broad scope of protection sought in the claims. Such is the case here where there is a
relatively incomplete understanding in the biotechnological field involved, as described above,
and the lack of a reasonable correlation between the narrow disclosure in the specification and
the broad scope of protection sought in the claims.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make or use the claimed invention. Therefore, claim 1 is not considered to be fully enabled by the instant disclosure.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Yue et al (Abstract title: AAV-SERCA2A EXPRESSION AMELIORATED CARDIOMYOPATHY IN THE MDX1, Article title: 15th International Congress on Neuromuscular Diseases July 6-10, 2018, Vienna, Austria, Journal of Neuromuscular Diseases, published on June 25th, 2018, Vol 5, Issue s1 pages S3-S383).
Yue et al discloses ameliorating cardiomyopathy in MDX mouse model of Duchenne Muscular Dystrophy through AAV-SERCA2A expression (see title). More specifically, Yue et al discloses administering an adeno-associated virus (AAV)-9 SERCA2a vector to 3-m-old mdx mice at the dose of 6E12 viral genome particles/mouse via the tail vein (Page S189, Column 2).
“Western blots and immunostaining confirmed robust SERCA2a expression in heart and skeletal muscle. Forelimb grip strength and treadmill running were significantly improved in treated mice. AAV-9 SERCA2a treatment also reduced the serum CK level, a marker of muscle damage. Importantly, SERCA2a treatment significantly improved heart function. Specifically, all ECG parameters were normalized to the wildtype levels. Conclusion: Our results suggest that AAV-9 SERCA2a gene therapy is a promising approach to treat DMD cardiomyopathy.” (Page S189, Column 2 to Page S190, Column 1).
Thus, instant claim 1 is anticipated by Yue et al.
Conclusion
No claim is allowed.
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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637