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 .
Election/Restrictions
Applicant’s election of Group III (claims 5-19) in the reply filed on June 15, 2026 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)).
The prior art relied upon in the rejection of the elected process claims 5-19 also discloses the product of claims 1 and 4 in Group I. Accordingly, no separate search burden remains between Groups I and III, and the provisional restriction requirement therebetween is withdrawn.
Claims 2-3, and 32 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II of invention, there being no allowable generic or linking claim.
Claims 1, 4-19 are pending and under examination.
Priority
Acknowledgment is made of applicant's claim for priority based on a US Provisional Application
No. 63/180,355 filed on 04/27/2021.
Specification
The disclosure is objected to because of the following informalities: The specification discloses that “increased [creatinine kinase] levels are a hallmark of muscle damage”, and “[w]hen elevated CK levels are found in a blood sample, it usually means muscle is being disintegrated by some abnormal process, such as muscular dystrophy or inflammation” ([95]). However, the term “creatinine kinase” is inconsistent with the terminology used in the art to describe the serum enzyme associated with muscle damage. For instance, Kim (Ann Rehabil Med, 2017, 41(2):306-312) teaches an increased level of serum creatine kinase is the hallmark of muscle damage, and patients with Duchenne Muscular Dystrophy (DMD) exhibits a markedly elevated creatine kinase level compared with the normal range, which has diagnostic value (pg. 307, col. 1, para. 2). Wyss (Physiological Reviews; 2000, 80(3):1107-1213) teaches creatine is nonenzymatically converted to creatinine (caption FIG. 4). Thus, the specification appears to refer to “creatine kinase” rather than “creatinine kinase”. Appropriate correction is required for this typographical error.
The disclosure is objected to because it contains an embedded hyperlink ([127]) and/or other form of browser-executable code. 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.
The use of the term “Alexa Fluor 488” ([135]), “Tween” ([133]), which is a trade name or a mark used in commerce, has been noted in this application. The term 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.
Information Disclosure Statement
The listing of references in the specification (e.g., [123]) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The IDS submitted on 05/31/2024 provided one single reference: Gushchina et al. This reference is crossed out because it is a duplicate of the Non-Patent Literature Document Cite No. 8 on the IDS filed 01/31/2024.
Claim Objections
Claim 6 is objected to because of the following informalities:
In claim 6, line 2, the acronym “DMD” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “DMD” is interpreted to mean “Duchenne Muscular Dystrophy”, as defined in the specification ([7]).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 6, 13-15, and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim 6 recites the limitation “the DMD gene” in line 2. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of a DMD gene in claim 5. Thus, it is unclear which DMD gene is referred to in claim 6.
Claim 13 recites the limitation "the level of functional dystrophin gene expression” in line 2, which renders the determination of the scope of the claim difficult. The specification does not define what constitutes “functional” dystrophin expression. The specification teaches different dystrophin proteins as a variety of in-frame mutations results in a variety of partially functional proteins ([91), including full-length dystrophin, truncated but functionally active isoform resulting from exon 2 skipping ([157]), and internally deleted but also functional dystrophin isoform resulting from exon 51 or exon 53 skipping (55]). As the dystrophin gene produces multiple dystrophin isoforms and a fully length dystrophin, and the specification identifies multiple forms of dystrophin as functional or partially functional, it is unclear which “functional” dystrophin gene and what degree of “functional” are referred to in claim 13.
Claims 13, 15, and 17 recite the limitation “the antisense oligonucleotide construct”. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of an antisense oligonucleotide construct in claim 5. It is noted that claim 5 only recites an oligonucleotide of claim 1 or a composition comprising the oligonucleotide, as embodiments of the antisense oligonucleotide construct were deleted from claim 5. Thus, it is unclear whether the antisense oligonucleotide construct recited in claims 13, 15, and 17 is related to the antisense oligonucleotide of claim 5.
Claim 15 recites “level of serum creatinine kinase” (emphasis added), and the specification discloses that “increased [creatinine kinase] levels are a hallmark of muscle damage”, and “[w]hen elevated CK levels are found in a blood sample, it usually means muscle is being disintegrated by some abnormal process, such as muscular dystrophy or inflammation” ([95]). However, in the art of muscular dystrophy, particularly, Kim (Ann Rehabil Med, 2017, 41(2):306-312) teaches an increased level of serum creatine kinase is the hallmark of muscle damage, and patients with Duchenne Muscular Dystrophy (DMD) exhibits a markedly elevated creatine kinase level compared with the normal range, which has diagnostic value (pg. 307, col. 1, para. 2). Further, creatinine and creatine kinase refer to different substances, particularly, Wyss (Physiological Reviews; 2000, 80(3):1107-1213) teaches creatine is nonenzymatically converted to creatinine (caption FIG. 4). Thus, the state of the art does not establish with reasonable certainty whether “creatinine kinase” recited in claim 15 and specification is intended to refer to creatine kinase, creatinine, and a different substance. The terminology used in the claims and specification is inconsistent with the art of muscular dystrophy. A person of ordinary skill in the art therefore would not be reasonably appraised of the scope of the claim, as it is unclear which substance’s serum level must be measured.
Claim 17 recites wherein muscular dystrophy progression in the subject is delayed after administering the oligonucleotide, as measured by the recited tests. Although the claim identifies administration of the oligonucleotide and tests as the measure of progression, the specification does not establish that change or pattern in these tests would constitute a “delay” in progression. In particular, it is unclear whether “delay” is determined by comparing to the subject’s progression before the treatment, an untreated population, or another reference. A statistical difference in progression between treated and control populations may demonstrate an effect of treatment at the population level, but does not establish whether progression in the particular subject is delayed. Thus, the specification does not provide a standard for one of ordinary skill in the art to determine whether muscular dystrophy progression has been “delayed”. Accordingly, one would not be reasonably apprised of the scope of the invention.
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 5-15, and 17-19 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 to treat Duchenne muscular dystrophy (DMD) in a subject having an exon 2 duplication in the DMD gene, comprising administering an oligonucleotide comprising the nucleotide sequence of SEQ ID NO: 1 or 2, does not reasonably provide enablement for a method to treat, prevent or ameliorate any muscular dystrophy in a subject comprising administering said oligonucleotide. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of the Claims
Claim 5 is directed to a method of treating a muscular dystrophy in a subject, comprising administering an oligonucleotide comprising the nucleotide sequence of SEQ ID NO: 1 or 2, or at least 95% sequence identity thereto. Thus, the breadth of claim 5 encompasses treatment, prevention, or amelioration of any muscular dystrophy, without requiring that the muscular dystrophy be Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD), be caused by a 5’ mutation in the DMD gene, or that muscular dystrophy involves an exon 2 duplication.
State of the Art
The state of the art establishes that treatment of a muscular dystrophy requires sequence-specific antisense oligonucleotides targeting the mutation and exon that causes the disease. Niks (Expert Opinion on Biological Therapy, 2017, 17(2):225-236) teaches that antisense-mediated exon skipping approach “needs to be tailored for different DMD mutation types” (abstract, para. 2). Niks further teaches examples of antisense-mediate exon skipping for mutation types including: deletion requiring double exon skipping, splice site mutation, small mutation in in-frame exon, small mutation in out-of-frame exon, exon duplication, and deep intronic mutation (Figure 2), each requiring antisense oligonucleotides comprising sequences specific to each targeted exon. Further, Becker muscular dystrophy (BMD) patients have mutations, e.g., deletion of exons 51 and 52, that maintain the reading frame and allow production of internally deleted but partially functional proteins (caption of Figure 1). In addition, Niks teaches that “while exon skipping would in theory apply to up to 81% of patients….it is anticipated that exon skipping will not result in functional dystrophins when mutations abolish all actin-binding domains, involve the dystroglycan binding domain and/or are deletions involving 36 exons or more” (pg. 228, col. 2, para. 3).
Aartsma-Rus (Nucleic Acid Therapeutics, 2017, 27(5):251-259) explains exon skipping is an approach to restore or increase dystrophin expression in DMD patients’ muscle fibers, but “different internally shortened dystrophins will be formed through exon skipping for patients with different deletions (e.g, the dystrophin formed after skipping exon 51 will differ for a deletion of exon 49-50 vs. a deletion of exon 52 and both will differ from the dystrophin formed after exon skipping for a deletion of exon 45)” (pg. 255, col. 1, para 5, (5)). Aartsma-Rus further discloses that “a clear relationship between the restoration of low levels of dystrophin and a functional outcome, clinically most important to the patients, has not been established so far” (pg. 255, col.2, para. 5).
Guidance of the Specification
The specification discloses Duchenne muscular dystrophy (DMD) results from 5' mutations in the DMD gene affecting any one or more of exons 1-5 ([75]). Further, the mutation could be a duplication of exon 2, and the claimed oligonucleotides comprising SEQ ID NO: 1 or 2 are sequence-specific oligonucleotides designed to interfere with splice acceptor site of exon 2 of the DMD gene, thereby induce exon 2 skipping and allow expression of a functional dystrophin protein ([61], [76]).The specification discloses working examples that administering SEQ ID NO: 1 as a cell penetrating peptide-conjugated phosphorodiamidate morpholino antisense oligonucleotide (referred to as PPMO-A1) in Dup2 mice results in exon 2 skipping and rescuing dystrophin expression in skeletal muscles ([4], Examples 2 and 3). The specification teaches that SEQ ID NO: 1 is "a promising therapeutic agent in the treatment of DMD patients with Dup2 mutations" ([157]). Thus, the therapeutic outcome depends on the presence of i) the particular DMD transcript comprising the specific 5' mutation, ii) exon 2 splice acceptor site, and iii) exon 2 duplication in which skipping produces a functional dystrophin protein.
The specification characterizes muscular dystrophies that differ in distribution and extent of muscle weakness, the age of onset, the rate of progression, and the pattern of inheritance ([5]). Particularly, Becker muscular dystrophy (BMD) "has a broad phenotypic spectrum" and a "variety of in-frame mutations resulting in a variety of partially functional proteins" ([92]), while DMD is caused by 5' mutations that disrupt the open reading frame in the DMD gene that encodes dystrophin ([91]). These teachings positively demonstrate that the mere identification of a disease as a muscular dystrophy does not establish that sequence-specific oligonucleotides comprising SEQ ID NO: 1 or 2 targeting exon 2 splice acceptor site will treat that disease.
Further, the disclosure is tied to correction of a mutant DMD gene and restoration of dystrophin ([123]) rather than prevention or amelioration of muscular dystrophy generally. There is no establishment that administration of SEQ ID NO: 1 or 2 before disease development prevents or ameliorates the onset of any arbitrary muscular dystrophy.
Accordingly, the specification does not provide adequate guidance commensurate with the full scope of the claims as the evidence of treatment is directed specifically to DMD associated with an exon 2 duplication. One ordinary skill in the art would not have been able to reasonably predict, without undue experimentation that administering instantly claimed oligonucleotide which targets the exon 2 splice acceptor site of the DMD gene, would treat, prevent, or ameliorate an arbitrary muscular dystrophy in a subject.
Experimentation Required
In order to practice the full scope of claimed invention, it would be necessary for one of ordinary skill in the art to perform the following undue experimentation, including but not limited to, (i) determine for each muscular dystrophy, whether the disease involves a targetable transcript corresponding to the claimed oligonucleotides that are specifically designed to target exon 2 splice acceptor site, (ii) determine whether exon 2 skipping of the DMD gene is relevant to that disease, and (iii) determine whether skipping the duplicated exon 2 would yield a functional dystrophin in that disease. The state of the art and the specification disclose antisense oligonucleotides are tailored for specific DMD mutation types; thus, results of the discussed undue experimentation could not be predicted based on oligonucleotides targeting one specific location, exon 2 splice acceptor site in the DMD gene.
In addition, the breath of the claimed invention is not limited to individuals having a DMD mutation amenable to exon 2 skipping. In the absence of such mutation, the specification or the state of the art does not provide basis for predicting that SEQ ID NO: 1 or 2 would prevent DMD or any muscular dystrophy. Thus, it would be necessary for one of ordinary skill in the art (i) to conduct studies in which the claimed oligonucleotide is administered before each disease onset, (ii) to determine whether the claimed method would any preventive effect across the broad scope of muscular dystrophy in the absence of the 5’ mutation in the DMD gene.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an unreasonable amount experimentation would be required to use the invention as claimed. Therefore, claims 5-15, and 17-19 are not considered to be fully enabled by the instant disclosure.
Claim Interpretation
Claim 15 recites “level of serum creatinine kinase”. The specification does not define “creatinine kinase”, but instead describes “increased [creatinine kinase] levels are a hallmark of muscle damage” and associates elevated levels of creatinine kinase to muscular dystrophy ([95]). In contrast, the art in the field of muscular dystrophy, particularly, Kim (Ann Rehabil Med, 2017, 41(2):306-312) identifies elevated creatine kinase as an indicator of muscle damage and diagnosis of Duchenne Muscular Dystrophy (pg. 307, col. 1, para. 2). Due to this recitation rendering the claim indefinite (see discussion above under 112(b)) and for purposes of compact prosecution, the term “creatinine kinase” is interpreted as creatine kinase, which is a hallmark for muscle damage in muscular dystrophy as consistent with the description provided in the disclosure and the terminology presented in the art.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1, 4-14, and 16-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Flanigan (US 2017/0218366 A1; Pub Date: Aug 03, 2017). The rejection of claim 8 is evidenced by Gushchina (Molecular Therapy, 2020, 28: 20; abstract 39; IDS received on 01/31/2024, NPL Cite No. 8).
Regarding claim 1, Flanigan teaches an “exon-2 targeting antisense oligomer, e.g., AL, comprises the nucleotide sequence of SEQ ID NO: 11, which is 100% identical to instant SEQ ID NO: 1 (sequence alignment shown below).
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Regarding claim 4, Flanigan teaches the exon-2 targeting antisense oligomer (i.e., oligonucleotide of claim 1) is comprised in a “DMD exon 5 IRES-activating oligomer construct” ([0053]). Flanigan further teaches the oligomer is comprised in a composition that also comprises a pharmaceutically acceptable carrier and diluents ([0066]).
Regarding claim 5, Flanigan teaches a method of treating Duchenne Muscular Dystrophy (DMD) associated with exon 2 duplication in the DMD gene in a subject in need thereof comprising the step of administering to the subject an effective amount of the oligonucleotide of claim 1 ([0053]).
Regarding claim 6, Flanigan teaches wherein the muscular dystrophy results from a 5’ mutation in the Duchenne Muscular Dystrophy (DMD) gene ([0053]).
Regarding claim 7, Flanigan teaches wherein the 5’ mutation is a mutation within or affecting 1, 2, 3, or 4 of the DMD gene ([0048])
Regarding claim 8, Flanigan teaches the AL antisense oligomer (i.e., instant SEQ ID NO: 1) is administered to “Dup2 mice” ([0101]). Flanigan also teaches a mdxdup2 mouse model that carries duplication of exon 2 within the DMD locus ([0090]). It is also evidenced by Gushchina that Dup2 mice carries “a duplication of exon 2, which is the most common single duplication mutation in DMD patients” (pg. 20, left-column). Although Flanigan states the method is for treating patients with a 5’ mutation in their DMD gene other than a DMD exon 2 duplication (abstract), it is noted that Example 10 demonstrate administration of the AL antisense oligomer into Dup2 mice and successfully achieved exon 2 skipping and efficient production and localization of dystrophin to the plasma membrane protein ([0102]). Thus, Flanigan anticipates the instant claimed method wherein the muscular dystrophy results from an exon 2 duplication.
Regarding claims 9 and 10, Flanigan teaches wherein the administering is via a systemic route by intramuscular injection into the tibialis anterior of Dup2 mice ([0102]).
Regarding claim 11, Flanigan teaches wherein the oligonucleotide is administered three doses weekly at 12mg/kg ([0103]).
Regarding claim 12, Flanigan teaches wherein the muscular dystrophy is DMD or Becker Muscular Dystrophy (BMD) ([0053]).
Regarding claim 13, Flanigan teaches that dystrophin is produced efficiently after administering the oligonucleotide (i.e., level of functional dystrophin protein expression in a cell of the subject is increased after administering the oligonucleotide) ([0102]).
Regarding claim 14, Flanigan further teaches wherein expression of functional dystrophin in the cell is detected by measuring the dystrophin protein level by immunostaining (i.e., immunohistochemistry) ([0102]).
Regarding claims 16 and 17, Flanigan teaches wherein muscle function in the subject is improved after administering the oligonucleotide, particularly, an improvement in muscle strength as determined by techniques known in the art such as maximal voluntary isometric contraction testing (MVICT) ([0055]).
Regarding claims 18 and 19, Flanigan teaches that the method further comprises administering a second therapy, particularly, a glucocorticoid ([0053]).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4-14, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Gushchina (Molecular Therapy, 2020, 28: 20; abstract 39; IDS received on 01/31/2024, NPL Cite No. 8) in view of Flanigan (US 2017/0218366 A1; Pub Date: Aug 03, 2017).
Regarding claims 1, and 4-5, Gushchina (entire abstract) teaches a method of treating Duchenne muscular dystrophy (DMD) associated with exon 2 duplication in the DMD gene, comprising administering a cell-penetrating peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO), i.e., oligonucleotide, targeting the exon 2 splice acceptor site in Dup2 mice, which carries a duplication of exon 2. Gushchina further teaches that the PPMO yields robust exon 2 skipping and expression of a functionally active dystrophin protein in both wild-type and Del2 transcripts, corresponding to skipping of a single copy or both copies of exon 2, respectively.
However, Gushchina does not teach wherein the oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 1.
Flanigan teaches a method of treating DMD associated with exon 2 duplication in the DMD gene in a subject in need thereof comprising the step of administering to the subject an effective amount of “a DMD exon 5 IRES-activating oligomer construct that is an exon 2-targeting antisense oligomer”, i.e., oligonucleotide ([0053]). One of the exemplary exon-2 targeting antisense oligomer, e.g., AL, comprises the nucleotide sequence of SEQ ID NO: 11, which is 100% identical to instant SEQ ID NO: 1 (sequence alignment shown above). Flanigan further teaches that the oligonucleotide targets the exon 2 splice acceptor site (SA), corresponding to positions -3 to +28, illustrated below ([0026]), FIG. 3B). Flanigan further demonstrates that administration of SEQ ID NO: 11 as a PPMO to Dup2 mice results in efficient exon 2 skipping, efficient dystrophin production and localization to the plasma membrane protein ([0103]). Flanigan also teaches SEQ ID NO: 11 is comprised in a composition with a pharmaceutically acceptable carrier and diluents ([0066]).
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Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the oligonucleotide of Gushchina to SEQ ID NO: 11 of Flanigan because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. The substitution would have been a simple replacement of one known PPMO targeting the exon 2 splice acceptor site with another known PPMO targeting the same site to perform the same function. It is merely swapping similar features to serve the same purpose. One would have had a reasonable expectation of success in doing so because Flanigan demonstrates the PPMO comprising SEQ ID NO: 11 successfully performs the same exon 2 skipping function resulting in expression of a functionally active dystrophin protein in the same Dup2 mouse model used by Gushchina.
Further, the selection of instant SEQ ID NO: 1 would have been an obvious-to-try alternative from a finite number of identified and predictable solutions. Gushchina identifies that exon 2 splice acceptor site as the target for exon 2 skipping but does not identify a particular oligonucleotide sequence. Flanigan teaches that oligonucleotides complementary to exon 2 splice acceptor site can be designed. Because the exon 2 splice acceptor site comprises a defined and limited nucleotide sequence, as illustrated by Flanigan in FIG. 3B (capitalized letters represent exon 2, lowercase letters represent splice site regions), the number of oligonucleotide sequences that could be designed to hybridize to that region if finite and readily ascertainable. Thus, one of ordinary skill in the art seeking an effective oligonucleotide targeting the exon 2 splice acceptor site to practice the method of Gushchina would have been motivated to select and test known or readily designable oligonucleotides directed to that site, including Flanigan’s SEQ ID NO: 11 that is identical to instant SEQ ID NO: 11.
Regarding claims 6-8, Gushchina teaches wherein the muscular dystrophy results from a 5’ mutation in the DMD gene, particularly, exon 2 duplication (the end of the abstract).
Regarding claims 9 and 10, Gushchina teaches wherein the administering is via a systemic route by intravenous injection into Dup2 mice (middle section of the abstract).
Regarding claim 11, Gushchina teaches a dose-escalation and time point studies are conducted in Dup2 mice, but the dosage is not explicitly stated.
Flanigan teaches wherein the oligonucleotide is administered three doses weekly at 12mg/kg ([0103]). Following the obviousness to modify Gushchina’s oligonucleotide to instant SEQ ID NO: 1 taught by Flanigan as discussed above and as applied to claim 5, it would have also been obvious to one to administer at a dosage taught by Flanigan because it would have merely amounted to a simple substitution to a refined dosage. One would have had a reasonable expectation of success in doing so because Flanigan demonstrated that administering at this dosage resulted in successful exon 2 skipping in the same Dup2 mice ([0103]).
Regarding claim 12, Gushchina teaches wherein the muscular dystrophy is DMD (beginning of the abstract).
Regarding claim 13, Gushchina teaches expression of the functionally active dystrophin increased after administering the oligonucleotide (end of the abstract).
Regarding claim 14, Gushchina further teaches wherein expression of functional dystrophin in the cell is detected by measuring the dystrophin protein level by western blot and immunofluorescence (end of the abstract).
Regarding claim 17, the obviousness to modify Gushchina’s oligonucleotide to instant SEQ ID NO: 1 taught by Flanigan as discussed above and as applied to claim 5. Flanigan teaches wherein muscle function in the subject is improved after administering the oligonucleotide, particularly, an improvement in muscle strength as determined by techniques known in the art such as maximal voluntary isometric contraction testing (MVICT) ([0055]).
Regarding claims 18 and 19, the obviousness to modify Gushchina’s oligonucleotide to instant SEQ ID NO: 1 taught by Flanigan as discussed above and as applied to claim 5.
Flanigan teaches that the method further comprises administering a combination therapy, particularly, a glucocorticoid ([0053]) as “treatment with glucocorticoids prednisone and deflazacort are standard treatment for DMD” ([0087]).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the method of Gushchina to further administer a combination therapy as taught by Flanigan because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Each component in the combination performs the same function as they do separately: oligonucleotide induces exon 2 skipping to restore expression of a functionally active dystrophin while the glucocorticoid slows muscle weakness. One would have been motivated to have done so for the advantage of practicing a dual-action approach for DMD, pairing muscle-preserving function with targeted exon skipping. One would have had a reasonable expectation of success in doing so because Flanigan teaches a method comprising administering both an oligonucleotide for exon 2 skipping and a combination therapy including glucocorticoids.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Flanigan (US 2017/0218366 A1; Pub Date: Aug 03, 2017) as applied to claim 5, and in view of T Hoen (US 2014/0088174 A1; Pub Date: Mar 27, 2014) and Kim (Ann Rehabil Med, 2017, 41(2):306-312).
Regarding claim 15, the teachings of Flanigan’s method of treating DMD comprising administering an oligonucleotide of SEQ ID NO: 11, that is 100% identical to instantly claimed SEQ ID NO: 1, are discussed above as applied to claim 5.
However, Flanigan does not teach measuring level of serum creatine kinase (CK) before and after administering the oligonucleotide to determine whether the level of CK expression is decreased.
T Hoen teaches a method for treating muscle loss or insufficient muscle growth that is a symptom of DMD, comprising administering a dystrophin exon-skipping nucleic acid, i.e., oligonucleotide ([0013]). T Hoen further teaches measuring improvement of muscle fiber function via detecting decrease of CK in blood ([0067]). T Hoen discloses that “a trend was observed of a decrease in serum CK levels, which is one of the indicators of muscle damage, in AON-treated mdx mice”, resulting in “a general improvement in the muscle fiber integrity upon treatment” (FIG. 22; [0212]), positively teaching that oligonucleotide treatment of mice suffering from DMD results in decrease levels of CK.
In addition, Kim explains why CK levels is a hallmark of muscle damage in in DMD patients (pg. 308, col. 1). Kim teaches that a lack of dystrophin, which provides structural stability to the muscle cell membrane, leads to increased permeability and consequently release of CK from muscle fibers (paragraph bridging pg. 307-308).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the method of Flanigan to include assays to detect decrease of serum CK levels as taught by T Hoen because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Each component in the combination performs the same function as they do separately: the oligonucleotide induces exon skipping to restore expression of a functionally active dystrophin to improve muscle fiber function, while the assay detects the decrease of serum CK levels, a hallmark indicator of muscle fiber function in DMD. One would have been motivated to have done so for the advantage of assessing alleviation of one or more symptoms of DMD. One would have had a reasonable expectation of success in doing so because T Hoen in view of Kim establishes that reduction of serum CK levels is a recognized and measurable outcome of functional dystrophin expression in dystrophic mice.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 5-15, and 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 15, and 27 of U.S. Patent No. 11,053,494 in view of Flanigan (US 2017/0218366 A1; Pub Date: Aug 03, 2017), Gushchina (Mol. Ther., 2020, 28:20; abstract 39) and T Hoen (US 2014/0088174 A1; Pub Date: Mar 27, 2014).
Regarding instant claim 5, patented claim 15 of ‘494 recites a method of ameliorating Duchenne Muscular Dystrophy or Becker Muscular Dystrophy in a patient with a 5’ mutation in a DMD gene, comprising administering a DMD exon 5 IRES-activating oligomer construct (i.e., oligonucleotide) that comprises the nucleotide sequence set forth in SEQ ID NO: 11, which is 100% identical to instant claimed SEQ ID NO: 1.
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Regarding instant claims 6-7, 12, and 17-19, patented claim 1 of ‘494 recites limitations of instant claims 6-7 and 12. ‘494 recites wherein the progression of a dystrophic pathology is inhibited in the patient (i.e., delayed) (claim 2), and wherein the muscle function, in muscle strength, is improved in the patient (claims 3-5). ‘494 also recites the method further comprising administering a glucocorticoid to the patient (claim 27).
Regarding instant 8, ‘494 recites the patient does not have a DMD exon 2 duplication (claim 1).
Flanigan teaches a method of treating a Duchenne muscular dystrophy associated with exon 2 duplication in a subject in need thereof comprising the step of administering to the subject an oligonucleotide of SEQ ID NO: 11 that is also 100% identical to instant claimed SEQ ID NO: 1 (sequence alignment provided above) ([0053], [0103]). Flanigan further teaches that the oligonucleotide targets the exon 2 splice acceptor site (SA), corresponding to positions -3 to +28 ([0026]), FIG. 3B). Flanigan further demonstrates that administration of SEQ ID NO: 11 as a cell-penetrating peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO), to Dup2 mice carrying an exon 2 duplication results in efficient exon 2 skipping, efficient dystrophin production ([0103], Example 8).
In addition, Gushchina (entire abstract) teaches a method of treating DMD comprising administering a PPMO targeting the exon 2 splice acceptor site in Dup2 mice that carries a duplication of exon 2. Gushchina further teaches that the PPMO yields robust exon 2 skipping and expression of a functionally active dystrophin protein in both wild-type and Del2 transcripts, corresponding to skipping of a single copy or both copies of exon 2, respectively.
Thus, it would have been obvious to one of ordinary skill in the art to have applied the method of ‘494 to a patient with an exon 2 duplication as taught by Flanigan and Gushchina because each prior art teaches that such method can be extended to other DMD patients carrying different types of 5’ mutations. Flanigan successfully demonstrate that administering instantly claimed SEQ ID NO: 1 in Dup 2 mice, carrying a duplication of exon 2, results in robust exon 2 skipping and efficient production of functional dystrophin protein to ameliorate DMD. Gushchina also supports Flanigan’s teachings by demonstrating oligonucleotides targeting exon 2 splice acceptor site yields similar results. Thus, one would have had a reasonable expectation of success in applying the method of ‘494 in patients comprising an exon 2 duplication.
Regarding instant claims 9-11, and 13-14, the obviousness to modify ‘494’s method to DMD patients’ carrying an exon 2 duplication as taught by Flanigan and Gushchina is discussed above as applied to claim 8.
Further, Flanigan teaches wherein the oligonucleotide is administered three doses weekly at 12mg/kg ([0103]) via a systemic route by intramuscular injection into the tibialis anterior of Dup2 mice ([0102]). Flanigan further teaches that dystrophin is produced efficiently after administering the oligonucleotide (i.e., level of functional dystrophin protein expression in a cell of the subject is increased after administering the oligonucleotide) ([0102]), as measured by immunostaining ([0102]).
Thus, it would have been obvious to one of ordinary skill in the art to further modify the method of ‘494 to administer the oligonucleotide at specific dosage and measure dystrophin expression levels by immunohistochemistry as taught by Flanigan because it would have merely amounted to simply following Flanigan’s suggestions to implement the method into practice. One would have been motivated to have done so for the advantage of implementing known parameters and avoiding unnecessary trial and error experimentation. One would have had a reasonable expectation of success in doing so because Flanigan teaches a method of treating DMD comprising administering an oligonucleotide comprising the instantly claimed sequence, and successfully achieved exon 2 skipping and restoration of dystrophin.
Regarding instant claim 15, ‘494 does not recite wherein the levels of serum creatine kinase (CK) is decreased after administering the oligonucleotide.
T Hoen teaches a method for treating muscle loss or insufficient muscle growth that is a symptom of DMD, comprising administering a dystrophin exon-skipping nucleic acid, i.e., oligonucleotide ([0013]). T Hoen further teaches measuring improvement of muscle fiber function via detecting decrease of CK in blood ([0067]). T Hoen discloses that “a trend was observed of a decrease in serum CK levels, which is one of the indicators of muscle damage, in AON-treated mdx mice”, resulting in “a general improvement in the muscle fiber integrity upon treatment” (FIG. 22; [0212]), positively teaching that oligonucleotide treatment of mice suffering from DMD results in decrease levels of CK.
Thus, it would have been obvious to one of ordinary skill in the art to have modified the method of ‘494 to include assays to detect decrease of serum CK levels as taught by T Hoen because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Each component in the combination performs the same function as they do separately: the oligonucleotide induces exon skipping to restore expression of a functionally active dystrophin to improve muscle fiber function, while the assay detects the decrease of serum CK levels, a hallmark indicator of muscle fiber function in DMD. One would have been motivated to have done so for the advantage of assessing alleviation of one or more symptoms of DMD. One would have had a reasonable expectation of success in doing so because T Hoen establishes that reduction of serum CK levels is a recognized and measurable outcome of functional dystrophin expression.
Claims 5-15, and 17-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-27, 37, and 39 of copending Application No. 17/335,251 in view of Flanigan (US 2017/0218366 A1; Pub Date: Aug 03, 2017), Gushchina (Mol. Ther., 2020, 28:20; abstract 39), and T Hoen (US 2014/0088174 A1; Pub Date: Mar 27, 2014).
Regarding instant claim 5, copending claim 37 of ‘251 recites a method of ameliorating Duchenne Muscular Dystrophy or Becker Muscular Dystrophy in a patient with a 5’ mutation in a DMD gene, comprising administering a DMD exon 5 IRES-activating oligomer construct (i.e., oligonucleotide) that comprises the nucleotide sequence set forth in SEQ ID NO: 11, which is 100% identical to instant claimed SEQ ID NO: 1.
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Regarding instant claims 6-15, and 17-19, ‘251 recites wherein the progression of a dystrophic pathology is inhibited in the patient (i.e., delayed) (claim 25), wherein muscle function, particularly muscle strength is improved (claims 26-27), and the method further comprises administering a glucocorticoid (claim 39). All remaining instant limitations are addressed because they are either recited in patented claims or are render obvious by prior art in view of Flanigan, Gushchina, and T Hoen to make the same modification based on the obviousness rationale as discussed above as applied to patented claims of U.S. Patent No. 11,053,494.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowable.
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/QIWEN SU-TOBON/
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights