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 without traverse of SEQ ID NO: 350 (SEQ ID NOs 604, 624, 640, 668, 670 and 684) in the reply filed on 11/17/25 is acknowledged.
The non-elected SEQ ID NOs: in Claims 1, 2, and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/17/25.
Specification
The use of the term “Lipofectamine RNAiMax” in paragraph 114 and “superscript III" in paragraph 115, 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. As a courtesy to the Office, please review the specification for any additional trademarks.
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 abstract of the disclosure is objected to because of the term “said” on line 3. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Claim Objections
Claims 23, 24 and 57 are objected to because of the following informalities: suggest adding the term “double homeobox 4” or “Facioscapulohumeral muscular dystrophy” before the abbreviation DUX4 or FSHD, respectively to help one skilled in the art understand the abbreviation.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 23-25 and 30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed method embraces ameliorating, preventing or delaying the onset of or treating a disease or disorder associated with aberrant expression of DUX4 in a subject in need thereof.
The prior art provides a limiting teaching of DUX4 associated diseases, including FSHD is the a disease or disorder associated with aberrant expression of DUX4. For example, see Lim et al. (Human Molecular Genetics, 2015, Vol. 24 Page 4817-4828 and Ansseau et al. (Genes 2017 8, 93, pages 1-21), both cited an IDS. A DUX4 inhibitor can be used to treat cancer. See WO 2020028134, cited on an IDS.
The specification teaches that FSHD is associated with aberrant expression of DUX4 (page 2) and does not appear to describe any additional diseases and/or disorders with DUX4 expression. The specification does not appear to describe any other disease or disorder embraced by the claimed method. By claiming any possible disease or disorder that might eventually be associated with aberrant DUX4 expression, the claimed method is trying to pre-empt the future before it has arrived. Other than FSHD, the specification does not have written support a genus of diseases or disorders associated with aberrant expression of DUX4.
FSHD is an autosomal dominant disorder characterized by progressive and asymmetric weakness of facial, shoulder and limb muscles. Symptoms typically arise in adulthood with most patients showing clinical features before age thirty. About five percent of patients develop symptoms as infants or juveniles and these are generally more severely affected. Clinical presentation can vary from mild (some limited muscle weakness) to severe (wheelchair dependence).
While the specification contemplates the preventing method a disease or disorder associated with aberrant expression of DUX4, the specification does not describe the method and materials and methods steps to carry out the preventing the disease or disorder. The prior art does not describe using a siRNA to prevent a disease or condition associated with aberrant expression of DUX in a subject in need thereof. While the specification contemplates the preventing method, the specification does not provide description of the actual steps for the method. It was not routine in the prior art to use a siRNA to prevent a disease or condition associated with aberrant expression of DUX in a subject in need thereof. The specification does not teach the end point of preventing the disease or disorder associated with aberrant DUX4 expression. How would a skilled artisan know if the disease or disorder was prevented or that the subject never developed the disease or disorder for another reason? Nucleic acid inhibitors are used in the prior art to reduce expression of a nucleotide sequence (e.g., gene or mRNA) to treat a disease or disorder and the sequence has to be expressed at a certain amount for the disease or disease to manifest. Neither the specification nor the prior art disclose how to screen for subjects that are at risk of the disease or disorder or might developed the disorder or disease. What time point or level of DUX4 expression is required in said subject to determine that the subject needs DUX4 siRNA before the disease occurs?
In view of the foregoing, it is clear that the specification of the instant disclosure fails to convey to the skilled artisan that the applicant had possession of the claimed genus of method of treating, ameliorating or preventing a DUX4 associated diseases in claims as of the effective filing date.
Claims 23-25 and 30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for ameliorating or delaying the onset of treating a disease or disorder associated with aberrant expression of DUX4 in a subject in need thereof, wherein the disease is Facisoscapulohumeral muscular dystrophy (FSHD) or cancer, does not reasonably provide enablement for preventing a disease or disorder associated with aberrant expression of DUX in a subject in need thereof. NOTE: the scope of enablement does not indicate that there is written support for the enabled scope (e,g., cancer). 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 specification contemplates the claimed method and provides working examples for using the claimed siRNA in cell lines. The specification shows that siRNA comprising SEQ ID NO: 350 or chemically modified versions of the siRNA, including a strand comprising SEQ ID NO: 604, 624, 640, 668, 670 and 684 showed a high percentage (97%) of inhibition of DUX expression in cell lines. See Tables 2 and 4.
The specification teaches that a DUX4 nucleotide sequence (including human genomic sequence) is known in the prior art. See pages 1, 2 and 26. The specification only teaches that FSHD is associated with aberrant expression of DUX4 (page 2).
The claims embrace a large number of diseases or disorders that at time of filing were not known to be associated with aberrant DUX4 expression, including non-muscular disorders (kidney, liver, cardiac, Alzheimer’s, Parkinson, cancer, etc.). The prior art teaches that FSHD and cancer appear to be the only disease or disorder known to be associated with aberrant expression of DUX4. FSHD is an autosomal dominant disorder characterized by progressive and asymmetric weakness of facial, shoulder and limb muscles. See Lim et al. (Human Molecular Genetics, 2015, Vol. 24 Page 4817-4828 and Ansseau et al. (Genes 2017 8, 93, pages 1-21), both cited an IDS. Both prior art references teach that one of skill in the art can administer a siRNA or an antisense oligonucleotide to a subject having FSHD and reduce aberrant expression of DUX4 to treat FSHD.
While the specification contemplates the preventing method, the specification does not provide a working example of the method. It was not routine in the prior art to use a siRNA to prevent a disease or condition associated with aberrant expression of DUX in a subject in need thereof. The specification does not teach the end point of preventing the disease or disorder associated with aberrant DUX4 expression. Symptoms of FSHD typically arise in adulthood with most patients showing clinical features before age thirty. About five percent of patients develop symptoms as infants or juveniles and these are generally more severely affected. Clinical presentation can vary from mild (some limited muscle weakness) to severe (wheelchair dependence). In view of the teaching in the prior art regarding FSHD, there are several enablement issued for preventing a disease or disorder associated with aberrant DUX4 expression, including; how would a skilled artisan know if the disease or disorder was prevented or that the subject never developed the disease or disorder for another reason? Nucleic acid inhibitors are used in the prior art to reduce expression of a nucleotide sequence (e.g., gene or mRNA) to treat a disease or disorder and the sequence has to be expressed at a certain level for the disease or disease to manifest. Neither the specification nor the prior art teach how to screen for subjects that are at risk of the disease or disorder or might developed the disorder or disease. What time point or level of DUX4 expression is required in said subject to determine that the subject needs DUX4 siRNA before the disease occurs? The specification does not teach what amount of the siRNA can be used to prevent the disease or disorder. Furthermore, other than contemplating treating or preventing any disease or disorder associated with aberrant expression of DUX4, administering DUX4 siRNA molecules to cell lines, the specification of the application does not disclose how to use the full scope of the claimed invention without an undue amount of experimentation. See Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: "Patent 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. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") 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." Applicant cannot rely on the knowledge of one skilled in the art to supply information on the novel aspects of the claimed invention. Thus, in view of the reasons set forth above, it would take an undue amount of experimentation for one of skill in the art to practice the full scope of the claimed invention.
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 1-2, 6-8, 11-15, 17, 23-25, 30, 37, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Harper et al. (US 20140322169) taken with Rigo (US20180273942, cited on an IDS).
Harper discloses DUX4 inhibitory RNA 19-mer oligonucleotide sequences that are 100% to SEQ ID NOs: 350 (Db) (SEQ ID NOs 604, 624, 640, 668, 670 and 684). See SEQ ID NOs: 1819 (Qy), 4001-2, 6181-6183, 8361, 8363, 8364 and 10539, 10540, 10541, 10543.
Qy 1 UCAUUCUGAAACCAAAUCU 19
Db 1 UCAUUCUGAAACCAAAUCU 19
The sequences are human DUX4 miRNA antisense guide strand. Harper suggest using these sequences to make a double stranded RNA comprising any of these sequences and a complementary sequence thereto (page 2). The DUX4 inhibitory RNA can be an antisense RNAs, small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), or artificial microRNAs. Page 9 of Harper discloses administering a composition comprising an AAV comprising a DUX4 miRNA encoding DNA to a cell to inhibit DUX4 expression and treat FSHD. Administration of an effective dose of the compositions may be by routes standard in the art including, but not limited to, intramuscular, parenteral, intravenous, oral, buccal, nasal, pulmonary, intracranial, intraosseous, intraocular (paragraph 31).
Harper teaches using an AAV to deliver a miRNA antisense guide strand to a cell or a subject, but does not specifically teach a siRNA having at least one chemically nucleoside
However, Rigo teaches using DUX4 siRNA to treat FSHD, FSHD 1 and 2 (pages 2-8 and 25-27). The siRNA can have an overhang (paragraph 116). The siRNA can comprise at least one modified nucleoside, which is selected from a 2′-F modified nucleoside or a 2′-OMe modified nucleoside. The sense strand of the siRNA can comprises at least 1 modified internucleoside linkage (at least 5 modified internucleoside linkages), wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage. A pharmaceutical composition comprising the siRNA and one or more tissue-specific deliver molecules (antibodies or liposomes) can be used to deliver the siRNA to specific tissues or cell types (paragraph 130). The siRNA can be administered to a subject using any suitable administration route including, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, intracerebroventricular, intraperitoneal, intranasal, and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous) (paragraph 138).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Harper taken with Rigo to make a chemically modified siRNA comprising a first strand comprising instant SEQ ID NO: 350 and another strand that is complementary to the first strand, and the siRNA having at least one modified nucleoside, namely to arrive at the claimed invention. See MPEP 2143(II)B or E. With respect to claim 37, while it is acknowledged that the SEQ ID NOs: listed in the claims are directed to chemically modified strands of the siRNA, the limitation ‘at least 8 contiguous nucleotides of the sequences’ does not limit the strand to these sequences because there is not a structural limitation excluding unmodified nucleotides of the SEQ ID NOs:. Thus, the siRNA made obvious by Harper and Rigo reads on the limitation in instant claim 37. In view of the teaching of Harper and Rigo, a person of ordinary skill in the art would have of had a reasonable expectation of success of making the siRNA using a sequence comprising SEQ ID NO: 350 and at least one modified nucleoside. One of ordinary skill in the art would have been motivated to combine the teaching to increase the stability or bioavailability of the siRNA in a cell or a subject and avoid having to make and use an AAV to deliver the siRNA. As taught by Rigo, it would have been obvious to modify at least one nucleoside of the sense strand of the siRNA with a 2’-OMe modified sugar or a 2’-F modified sugar or at least one modified internucleoside linkage (phosphorothioate) to study the efficacy or bioavailability of the siRNA in a cell or a subject. Rigo teaches the siRNA having at least five phosphorothioate internucleoside linkage. It would have been obvious to one of ordinary skill in the art to try a modified sugar or a phosphorothioate internucleoside linkage at each nucleoside of the sense strand to determine the optimal stability and/or efficacy of the siRNA in reducing DUX4 expression. Rigo teaches conjugating the siRNA to a lipid to assist in delivery of the siRNA to a cell, wherein the lipid comprises cationic lipids and neutral lipids (paragraph 127). Cationic lipids are long chain fatty acids and be used to increase distribution of the siRNA to muscle tissue. A person of ordinary skill in the art would have been motivated to make a composition comprising the siRNA comprising the instant SEQ ID NO: 350 and a pharmaceutically acceptable carrier to deliver the siRNA to a subject. Rigo teach using DUX4 siRNA to treat FSHD1 or 2 in a subject in need thereof. Rigo teaches using the delivery routes in instant claim 30 to deliver a siRNA to the subject.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 9 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Harper et al. (US 20140322169) taken with Rigo (US20180273942, cited on an IDS) as applied to claims 1-2, 6-8, 11-15, 17, 23-25, 30, 37, and 57 above, and further in view of Dharmacon (Technical Bulletin #003-Revision A siRNA oligonucleotides for RNAi applications, 2001, pages 1-12).
Harper and Rigo do not specifically teach either strand of the siRNA having a TT overhang.
However, overhangs in the 3’ end of the sense/antisense strand including dTdT were routinely used in the prior art to increase stability of a siRNA in a cell. See page 2 of Dharmacon.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Harper and Rigo taken with Dharmacon to add a TT to the terminal end of the antisense/sense strand of the siRNA, namely to arrive at the claimed invention. See MPEP 2143(II)E. One of ordinary skill in the art would have been motivated to combine the teaching to reduce nuclease degradation in a cell and/or to study the stability and efficacy of the siRNA.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Harper et al. (US 20140322169) taken with Rigo (US20180273942 cited on an IDS) as applied to claim 1-2, 6-8, 11-14, 17, 23-25, 30, 37, and 57 above, and further in view of Dyne Therapeutics (WO 2020/0288645, filed on 8/2/18 and published on 2/26/20).
Harper and Rigo do not specifically teach conjugated the siRNA to an anti-transferrin antibody.
However, ‘645 teach that anti-transferrin antibody is a muscle targeting agent and can be used to deliver a nucleic acid (antisense oligonucleotide that targets DUX4) to muscle cells.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Harper and Rigo taken with ‘645 to conjugate the siRNA to an anti-transferrin antibody, namely to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to combine the teaching to assist in delivery of the siRNA to a muscle cells of a subject.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Conclusion
See attached PTO-326 for disposition of claims.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Khvorova et al. (US 20070031844) discloses several algorithms for making siRNA and generated millions of siRNA based on the algorithms. One sequence comprising SEQ ID NO: 813084 (Db) reads on instant SEQ ID NO: 350, but ‘844 does teach what is the definition of SEQ ID NO: 813084 or what algorithm was used to make this SEQ ID NO: or if it is a siRNA what gene the siRNA targets. In addition, the sequence does not comprise at least one modified nucleoside and there is no teaching or suggesting in the disclosure of ‘844 for using the sequence in a siRNA to reduce DUX4 expression in a cell. Qy is SEQ ID NO: 350.
Qy 1 UCAUUCUGAAACCAAAUCU 19
Db 19 TCATTCTGAAACCAAATCT 1
A 103 rejection based on ‘844 is not required because the instant claims are already rejected under 103.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571)-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636