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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/30/2026 has been entered.
Claim(s) 1, 10-17, and 25-28 are pending.
Applicant’s arguments filed 02/27/2026 have been thoroughly reviewed, but are not persuasive for the reasons that follow. Any rejections and objections not reiterated in this action have been withdrawn. This action is non-final.
Election/Restrictions
Applicant’s election without traverse of the species, 1= siRNA and 2= no additional components in the reply filed on 04/10/2025 is acknowledged. Examiner maintains the species election of SCN11A inhibitor which the Applicant elected “siRNA”. However, the species requirement of a “therapeutic agent” in which the Applicant elected “no additional components” has been withdrawn. This withdrawal does not change the status of the current claim set filed 02/27/2026.
Claim(s) 1, 10-17, and 25-28 are under consideration
Priority
Acknowledgement is made of Applicant’s claim for priority based on a provisional application filed as 63/281,640 on 11/20/2021.
All claims are given the priority date of 11/20/2021.
Information Disclosure Statement
Receipt of the information disclosure statement on 05/01/2025 is acknowledged. The signed and initialed PTO-1449 form(s) has/have been mailed with this action.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
In the “Reference to Sequence Listing” paragraph, the size of the XML file is listed in kilobytes, not bytes.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities. This is a new specification objection:
“Odds Ration” in column 2 of Table 1 on page 66 should recite “Odds Ratio”.
The acronyms provided in the table on page 66 do not have definitions associated with them. One of ordinary skill in the art would not be able to understand what is being measure and/or labeled:
Column 2 (LCI, UCI);
Colum 4 (AAF); and
Column 5 and 6 (RR, RA, AA);
For ease of correction, a paper in which one of the instant inventors is the corresponding author on, Akbari et al (Sequencing of 640,00 exomes identifies GPR75 variants associated with protection from obesity, Science, Volume 373, Pages 1-11, Published July 2nd, 2021) defines these acronyms:
“Abbreviations: CI, confidence interval; SD, standard deviation; BMI, body mass index; AAF, alternative allele frequency; RR, reference-reference genotype; RA, reference-alternative heterozygous genotype; AA, alternative-alternative homozygous genotype; …”, (see table 1 figure legend at the top of page 2).
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim(s) 14-17 and 25-28 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and law of nature without significantly more. This is a new rejection.
Step 2A: Prong One.
The independent claim recites “…determining whether the subject has a Sodium Voltage-Gated Channel Alpha Subunit 11 (SCN11A) predicted loss-of-function variant nucleic acid molecule by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the SCN11A predicted loss-of-function variant nucleic acid molecule; …” These steps read on “determining” via the steps of “having obtained… and having performed…” by looking at a genotype printed on a piece of paper or displayed on a computer screen or thinking about acts having been carried out in the past. The “determining” via the steps of “having obtained… and having performed” recite an embodiment where the claim limitation is practically performed in the mind. Thus, the steps fall within the Mental Process group of abstract ideas. Dependent claim 17 does not require one to actively carry out the steps by limiting the claims to only active steps rather than steps that have been carried out in the past. The dependent claim reads on an embodiment where one is only thinking about the genotype.
The independent claim recites “… wherein the presence of a genotype having the SCN11A predicted loss-of-function variant nucleic acid molecule indicates the subject has a decreased risk of developing a headache or migraine” This is a natural law of correlation.
Step 2A: Prong Two.
The judicial exception is not integrated into a practical application. The independent claim as a whole, looking at the additional elements individually and in combination, does not integrate the judicial exception into a practical application.
The independent claim recites the additional limitation “administering or continuing to administer the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in a standard dosage amount to a subject that is SCN11A reference, and/or administering an SCN11A inhibitor to the subject; administering or continuing to administer the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in an amount that is the same as or less than a standard dosage amount to a subject that is heterozygous for the SCN11A predicted loss-of-function variant nucleic acid molecule, and/or administering an SCN11A inhibitor to the subject; or administering or continuing to administer the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in an amount that is the same as or less than a standard dosage amount to a subject that is homozygous for the SCN11A predicted loss-of-function variant nucleic acid molecule…”. This limitation reads on an embodiment where the subject, independent of the genotype, is continuing to be administered a general therapeutic agent at the standard dosage. The administered treatment is not a particular treatment that relies upon the judicial exception(s) in a meaningful way because the same treatment is applied regardless of genotype.
Dependent claim 15 limits the claim 14 and recites, “wherein the subject is SCN11A reference, and the subject is administered or continued to be administered the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in a standard dosage amount, and is administered the SCN11A inhibitor.” Dependent claim 16 limits claim 14 and recites, “wherein the subject is heterozygous for SCN11A predicted loss-of-function variant nucleic acid molecule, and the subject is administered or continued to be administered the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in an amount that is the same as or less than a standard dosage amount, and is administered the SCN11A inhibitor.” Both, claim 15 and 16 are consider general and not particular treatments. MPEP 2106.04(d)(2) recites: The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). Thus, the administration step does not integrate the mental analysis step or law of nature into a practical application.
Dependent claim(s) 25 and 27 limit claim 14 as a whole, i.e., wherein the subject has a headache or wherein the subject has a migraine, respectively. However, these limitations merely indicate a field of use/technological environment.
Dependent claim 26 is dependent on claim 25 and recites, “wherein the therapeutic agent is chosen from a nonsteroidal anti-inflammatory drug, acetaminophen, celecoxib, diclofenac, fenoprofen, indomethacin, ketorolac tromethamine, meclofenamate sodium, diflunisal, tolmetin, ketoprofen, and flurbiprofen, or any combination thereof.” This limitation is considered general and not particular. Claim 26 limits claim 25, which limits claim 14. The claim reads on an embodiment where a subject with a headache is administered a therapeutic agent regardless of the genotype of the subject. Thus, limiting the therapeutic agent to a general list for subjects with a headache, regardless of genotype, does not integrate the mental analysis step or law of nature into a practical application.
Dependent claim 28 is dependent on claim 27 and recites, “wherein the therapeutic agent is chosen from a nonsteroidal anti-inflammatory drug, acetaminophen, a triptan, an ergot, a calcitonin gene-related peptide (CGRP) receptor antagonist, an anti-nausea agent, a high blood pressure medication, an antidepressant, an antiseizure medication and botox, or any combination thereof.” This limitation is considered general and not particular. Claim 28 limits claim 27, which limits claim 14. The claim reads on an embodiment where a subject with a migraine is administered a therapeutic agent, regardless of the genotype of the subject. Thus, limiting the therapeutic agent to a general list for subjects with a migraine, regardless of the genotype, does not integrate the mental analysis step or law of nature into a practical application.
Step 2B
The independent claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception. As mentioned in Step 2A: Prong Two above, the independent claim recites the additional limitation of “administering or continuing to administer the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in a standard dosage amount to a subject that is SCN11A reference, and/or administering an SCN11A inhibitor to the subject; administering or continuing to administer the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in an amount that is the same as or less than a standard dosage amount to a subject that is heterozygous for the SCN11A predicted loss-of-function variant nucleic acid molecule, and/or administering an SCN11A inhibitor to the subject; or administering or continuing to administer the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in an amount that is the same as or less than a standard dosage amount to a subject that is homozygous for the SCN11A predicted loss-of-function variant nucleic acid molecule…” The administering steps are routinely used by those of ordinary skill in the art. “Continuing to administer” a “standard dosage” of a therapeutic agent, such as ibuprofen (listed on page 48 of the specification) is well-understood, routine, and conventional activity in the art. When looking to Advil® (How Much Ibuprofen Can I Take? | AdvilSymptoms; www.advil.com/symptoms-tips/pain/how-much-ibuprofen-can-i-take/) for “How much ibuprofen can I take?”.
Advil® discloses, “Ibuprofen is a medication that’s widely used to relieve pain. As the active ingredient in Advil, it provides effective relief for a variety of conditions, from headaches and muscle aches to cold, flu and sinus symptoms. If you’ve been wondering “How much ibuprofen should I take?” - you’ve come to the right place. Learn about ibuprofen dosage and how physical factors can impact effectiveness. The amount of ibuprofen that you can take in a day depends on the strength of the medicine and what you’re taking it for. Adults treating menstrual cramps or mild aches and pain can take 400mg every 4-6 hours as needed. However, adults and teens who are treating rheumatoid or osteoarthritis may be directed by their healthcare provider to take 1200mg up to 3200mg per day, divided into three or four equal doses. Where children are concerned, the ibuprofen dose is often determined by age or body weight when treating pain or fever. Follow the directions of your healthcare provider to ensure you’re taking the right amount for what you need and that you’re not taking too much. For OTC ibuprofen products for children and adults, always follow the dosing directions in the Drug Facts label box on the product packaging.”.
Thus, the additional elements do not add significantly more. The claim(s) as a whole does/do not amount to significantly more than a judicial exception.
Accordingly, claim(s) 14-17 and 25-28 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature without significantly more.
Claim Rejections - 35 USC § 112(b) – Indefiniteness
Response to amendments:
The previous rejection of claim(s) 1, 3-4, 10-19, and 25-28 under 35 U.S.C 112(b) for containing the feature “at risk” has been withdrawn in view of Applicant’s amendments to the claims filed 02/27/2026.
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.
Claim(s) 11-12, 14-17, and 25-28 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. This is a new rejection.
Regarding claim(s) 11, 14, and 15, the term “standard dosage amount” is a relative term which renders the claim indefinite. The term “standard dosage amount” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claim(s) 12, 14, and 16, the term “…amount that is the same as or less than a standard dosage amount” is a relative term which renders the claim indefinite. The term “…amount that is the same as or less than a standard dosage amount” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Combined reasoning for the indefiniteness of “standard dosage amount” and “…amount that is the same as or less than a standard dosage amount” is described below.
The term(s) “standard dosage amount” and “…amount that is the same as or less than a standard dosage amount” are refereeing to an amount of “therapeutic agent” that is to be administered to a subject. To understand a dosing regimen or standard, one must be familiar with the agent that is being utilized for therapeutic treatment.
The specification defines “therapeutic agent”:
“Examples of therapeutic agents that treat or prevent a headache include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs) (such as, for example, aspirin, ibuprofen, fenoprofen, flurbiprofen, ketoprofen, and naproxen sodium), acetaminophen, celecoxib, diclofenac, indomethacin, ketorolac tromethamine, meclofenamate sodium, diflunisal, tolmetin, nabumetone, carisoprodol, orphenadrine citrate, methocarbamol, cyclobenzaprine hydrochloride, metaxalone, prednisone, ergotamine, lithium, propranolol, diltiazem, and an opioid, or any combination thereof.
Examples of therapeutic agents that treat or inhibit a migraine include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs) (such as, for example, aspirin, ibuprofen, fenoprofen, flurbiprofen, ketoprofen, and naproxen sodium); acetaminophen; diclofenac; ketorolac; propofol; Lasmiditan; a combination of aspirin, acetaminophen, and caffeine) a combination of isometheptene, dichloralphenazone, and acetaminophen; a triptan (such as, for example, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, donitriptan, sumatriptan, zolmitriptan, LY-334370, and L-694247); an ergot (such as, for example, dihydroergotamine and ergotamine tartrate); a calcitonin gene-related peptide (CGRP) receptor antagonist (such as, for example, rimegepant, atogepant, ubrogepant, eptinezumab, erenumab, fremanezumab, and galcanezumab); an anti-nausea agent (such as, for example, chlorpromazine, droperidol, metoclopramide, and prochlorperazine); a high blood pressure medication (such as, for example, a beta-blocker (such as, for example, propranolol, timolol, and metoprolol) and a calcium channel blocker (such as, for example, verapamil); an antidepressant (such as, for example, amitriptyline and nortriptyline); an antiseizure medication (such as, for example, gabapentin, topiramate, and valproic acid); an opioid; a barbiturate; feverfew; and botulinum toxin.”, (see page 48, lines 9-29, to page 49, lines 1-2).
The specification defines “standard dosage amount” and “less than a standard dosage amount” as:
“In some embodiments, the dose of the therapeutic agents that treat, prevent, or inhibit a headache or a migraine can be decreased by about 10%, by about 20%, by about by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, or by about 90% for subjects that are heterozygous for an SCN11A predicted loss-of-function variant nucleic acid molecule (i.e., a less than the standard dosage amount) compared to subjects that are SCN11A reference (who may receive a standard dosage amount). In some embodiments, the dose of the therapeutic agents that treat, prevent, or inhibit a headache or a migraine can be decreased by about 10%, by about 20%, by about 30%, by about 40%, or by about 50%. In addition, the subjects that are heterozygous for an SCN11A predicted loss-of-function variant nucleic acid molecule can be administered less frequently compared to subjects that are SCN11A reference.”, (see page 49, lines 3-13).
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Each therapeutic agent has a different “standard” of dosage, and even the same agent may have different standards of dosing depending on how severe the pain associated with the headache or migraine is. For example, GoodRx (Ketorolac Dosages for Adults: Your GoodRx Guide; Written by Austin Ulrich; published November 2nd, 2023) discloses that Ketorolac has different dosage forms and strengths depending on age, and other factors such as body weight and/or kidney problems (see table below).
Claim(s) 17 and 25-28 are rejected for being dependent on claim 14.
Claim Rejections - 35 USC § 112(a) – 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(s) 1, 10-17, and 25-28 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. This rejection was made in the Office action filed on 12/29/2025, and has been rewritten to address the amendment to the claims in the reply filed 02/27/2026.
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(s) 1, 10-17, and 25-28 are drawn to the genera of (1) “SCN11A inhibitory nucleic acid”, and (2) “therapeutic agent”, for treating a subject having a headache or a migraine. The rejected claims thus comprise a genus of either (a) SCN11A inhibitory nucleic acid and further comprising administering a therapeutic agent, or (b) a therapeutic agent and/or a SCN11A inhibitory nucleic acid, and are defined as belonging to the broad class of SCN11A inhibitory nucleic acids and therapeutic agents and as having the function of treating a subject having a headache or migraine and decreasing expression of the SCN11A polypeptide in a cell in the subject.
Claim(s) 1 and 14 limit the inhibitory nucleic acid molecule that hybridizes to an SCN11A mRNA molecule to an antisense nucleic acid molecule, a small interfering RNA (siRNA), and/or a short hairpin RNA (shRNA). Accordingly, claim(s) 1 and 14 are drawn to a subgenus defined by antisense nucleic acid molecule, a siRNA (elected speices), and/or a shRNA that must function as treating a subject having a headache or migraine and decreasing expression of the SCN11A polypeptide in a cell in the subject.
Claim(s) 26 and 28 limit the therapeutic agent to a nonsteroidal anti-inflammatory drug, acetaminophen, celecoxib, diclofenac, fenoprofen, indomethacin, ketorolac tromethamine, meclofenamate sodium, diflunisal, tolmetin, ketoprofen, and flurbiprofen, or any combination thereof (of claim 26), and a nonsteroidal anti-inflammatory drug, acetaminophen, a triptan, an ergot, a calcitonin gene-related peptide (CGRP) receptor antagonist, an anti-nausea agent, a high blood pressure medication, an antidepressant, an antiseizure medication and botox, or any combination thereof (of claim 28). Accordingly, claim(s) 26 and 28 are drawn subspecies defined by the list of therapeutic agents above that must function as treating a subject having a headache or migraine and decreasing expression of the SCN11A polypeptide in a cell in the subject.
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 specification envisions the inhibitory nucleic acid molecule that hybridizes to an SCN11A mRNA molecule (i.e., antisense nucleic acid molecule, a small interfering RNA (siRNA), and/or a short hairpin RNA (shRNA)) as:
“In some embodiments, the SCN11A inhibitor comprises an inhibitory nucleic acid molecule. Examples of inhibitory nucleic acid molecules include, but are not limited to, antisense nucleic acid molecules, small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs). Such inhibitory nucleic acid molecules can be designed to target any region of an SCN11A nucleic acid molecule. In some embodiments, the antisense RNA, siRNA, or shRNA hybridizes to a sequence within an SCN11A genomic nucleic acid molecule or mRNA molecule and decreases expression of the SCN11A polypeptide in a cell in the subject. In some embodiments, the SCN11A inhibitor comprises an antisense molecule that hybridizes to an SCN11A genomic nucleic acid molecule or mRNA molecule and decreases expression of the SCN11A polypeptide in a cell in the subject. In some embodiments, the SCN11A inhibitor comprises an siRNA that hybridizes to an SCN11A genomic nucleic acid molecule or mRNA molecule and decreases expression of the SCN11A polypeptide in a cell in the subject. In some embodiments, the SCN11A inhibitor comprises an shRNA that hybridizes to an SCN11A genomic nucleic acid molecule or mRNA molecule and decreases expression of the SCN11A polypeptide in a cell in the subject.”, (see page 35, lines 18-30 and page 36 lines 1-2).
“The inhibitory nucleic acid molecules can comprise RNA, DNA, or both RNA and DNA. The inhibitory nucleic acid molecules can also be linked or fused to a heterologous nucleic acid sequence, such as in a vector, or a heterologous label. For example, the inhibitory nucleic acid molecules can be within a vector or as an exogenous donor sequence comprising the inhibitory nucleic acid molecule and a heterologous nucleic acid sequence. The inhibitory nucleic acid molecules can also be linked or fused to a heterologous label…”, (see page 35 lines 3-8).
“The inhibitory nucleic acid molecules can comprise, for example, nucleotides or non-natural or modified nucleotides...”, (see page 36 lines 27-30 and page 37 lines 1-2).
“The inhibitory nucleic acid molecules can also comprise one or more nucleotide analogs or substitutions… Nucleotide analogs can also be modified at the phosphate moiety… In some embodiments, the antisense nucleic acid molecules are gapmers, whereby the first one to seven nucleotides at the 5' and 3' ends each have 2'-methoxyethyl (2'-MOE) modifications… In some embodiments, the siRNA molecules have termini modifications… In some embodiments, the siRNA molecules have backbone modifications… In some embodiments, the modified phosphodiester groups that link consecutive ribose nucleosides have been shown to enhance the stability and in vivo bioavailability of siRNAs… In some embodiments, a representative siRNA has the following formula: Sense: mN*mN*/2FN/mN/2FN/mN/i2EN/mN/i2FN/mN/i2FN/mN/12FN/mN/i2FN/mN/ i2FN/*mN*/32FN/ Antisense:/52FN/*/i2FN/*mN/i2FN/mN/i2EN/mN/2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/ i2FN/mN/i2FN/mN*N*N wherein: "N" is the base; "2F" is a 2'-F modification; "m" is a 2'-O-methyl modification, "I" is an internal base; and "*" is a phosphorothioate backbone linkage.”, (see pages 37-39).
“Percent identity (or percent complementarity) between particular stretches of nucleotide sequences within nucleic acid molecules or amino acid sequences within polypeptides can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs (Altschul et al., J. Mol. Biol., 1990, 215, 403-410; Zhang and Madden, Genome Res., 1997, 7, 649-656) or by using the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482-489). Herein, if reference is made to percent sequence identity, the higher percentages of sequence identity are preferred over the lower ones.”, (page 64, lines 4-13).
Applicant discloses a table starting on page 7 and ending on page 34 lists predicted loss-of-function variant nucleic acid molecules of SCN11A associated with migraines.
The specification envisions the therapeutic agent as:
“Examples of therapeutic agents that treat or prevent a headache include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs) (such as, for example, aspirin, ibuprofen, fenoprofen, flurbiprofen, ketoprofen, and naproxen sodium), acetaminophen, celecoxib, diclofenac, indomethacin, ketorolac tromethamine, meclofenamate sodium, diflunisal, tolmetin, nabumetone, carisoprodol, orphenadrine citrate, methocarbamol, cyclobenzaprine hydrochloride, metaxalone, prednisone, ergotamine, lithium, propranolol, diltiazem, and an opioid, or any combination thereof.
Examples of therapeutic agents that treat or inhibit a migraine include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs) (such as, for example, aspirin, ibuprofen, fenoprofen, flurbiprofen, ketoprofen, and naproxen sodium); acetaminophen; diclofenac; ketorolac; propofol; Lasmiditan; a combination of aspirin, acetaminophen, and caffeine) a combination of isometheptene, dichloralphenazone, and acetaminophen; a triptan (such as, for example, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, donitriptan, sumatriptan, zolmitriptan, LY-334370, and L-694247); an ergot (such as, for example, dihydroergotamine and ergotamine tartrate); a calcitonin gene-related peptide (CGRP) receptor antagonist (such as, for example, rimegepant, atogepant, ubrogepant, eptinezumab, erenumab, fremanezumab, and galcanezumab); an anti-nausea agent (such as, for example, chlorpromazine, droperidol, metoclopramide, and prochlorperazine); a high blood pressure medication (such as, for example, a beta-blocker (such as, for example, propranolol, timolol, and metoprolol) and a calcium channel blocker (such as, for example, verapamil); an antidepressant (such as, for example, amitriptyline and nortriptyline); an antiseizure medication (such as, for example, gabapentin, topiramate, and valproic acid); an opioid; a barbiturate; feverfew; and botulinum toxin.”, (see page 48, lines 9-29, to page 49, lines 1-2).
There are no examples provided for, in the specification, that meet the claim limitations of the rejected claims in regard to structure. The lack of results for a singular (1) inhibitory nucleic acid molecule that hybridizes to an SCN11A mRNA molecule (regarding length, modifications, or percent complementary) or (2) therapeutic agent in an art accepted model of any form of a headache or migraine proves to be not predictive of any/all inhibitory nucleic acid molecule that hybridizes to an SCN11A mRNA molecule and/or any/all therapeutic agents capable of treating a subject having a headache or migraine and decreasing expression of the SCN11A polypeptide in a cell in the subject. Thus, it is impossible for one to extrapolate that the inhibitory nucleic acid molecule that hybridizes to an SCN11A mRNA molecule (e.g., antisense nucleic acid molecule, siRNA, or shRNA) and/or a therapeutic agent described above would above would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of (1) inhibitory nucleic acid molecule that hybridizes to an SCN11A mRNA molecule (e.g., antisense nucleic acid molecule, siRNA, or shRNA) and (2) therapeutic agent, capable of treating a subject having a headache or migraine and decreasing expression of the SCN11A polypeptide in a cell in the subject.
Looking to the art on “inhibitory nucleic acid molecule that hybridizes to an SCN11A mRNA molecule (e.g., antisense nucleic acid molecule, siRNA, or shRNA)” Yu et al (Antisense-Mediated Knockdown of Nav1.8, but not Nav1.9, Generates Inhibitory Effects on Complete Freund’s Adjuvant-Induced Inflammatory Pain in Rat, Plos One, Volume 6, Issue 5, Pages 1-9, Published May 10th, 2011) describes one inhibitory nucleic acid molecule that hybridizes to SCN11A gene structure for the purposes of treating rats in CFA-induced pain.
Yu et al discloses the activation of Nav1.8 and Nav1.9 at the mRNA and protein level with Complete Freund’s Adjuvant (CFA) treatment (see Figure 1A-F). Yu et al discloses successful knock down of NaV1.9 in DRG neurons from naïve and CFA treated rats (see Figure 3 A-C). However, when looking at pain hypersensitivity, only the Nav1.8 antisense reversed the CFA-induced pain, and the Nav1.9 antisense did not (see Figure 4 A-B and Figure 5 A-B).
Yu et al concludes, “First, CFA inflammation treatment caused increased expressions of NaV1.8 and NaV1.9 in primary sensory DRG neurons. Functional analysis on the different components of voltage-gated sodium currents [25,26] demonstrated that CFA treatment significantly increased the sodium current densities of NaV1.8 and NaV1.9, but had no effects on TTX-S sodium currents. Second, intrathecal administration of NaV1.8 and NaV1.9 AS ODN significantly decreased CFA-induced proteins up-regulation and functional enhancement of TTX-R sodium channels. Third, behavioral tests showed that NaV1.8, but not NaV1.9, AS ODN could reverse CFA-induced heat and mechanical hypersensitivity. Our data indicated that the key pain modulators NaV1.8 and NaV1.9 played distinct regulations on the processing of CFA-induced inflammatory pain and that antisense oligodeoxynucleotide-mediated blocking of NaV1.8 over-expression might point toward a potential treatment strategy against certain types of pathological pain.”, (see Discussion, paragraph 1 starting on page 4).
For the oligodeoxynucleotides (AS ODNS), Yu et al discloses, “NaV1.8 and NaV1.9 were previously reported [20] and the sequences were 5’-TCCTCTGTGCTTGGTTCTGGCCT-3’ and 5’- GCCTTGTCTTTGGACTTCTTC-3’, respectively... ”, (The fluorescence labeling of ODNs were carried out by conjugation of carboxy fluorescein (FAM) to the 59 end of the ODNs, and synthesized as phosphodiester ODNs using standard O-cyanoethylphosphoramidite chemistry (Shanghai Sanggon Biological Engineering Technology Services Co., Ltd, China). Intrathecal (i.t.) delivery method was previously described [48] and ODNs (45 mg/5 ml, dissolved in nuclease-free ultrapure water) were i.t. administered twice daily for three consecutive days.”, (see pages 6-7 under Antisense oligodeoxynucleotide delivery).
Looking to the art for “therapeutic agent” WebMD (Migraine Headache Treatment, Written by WebMD Editorial Contributors, Published January 20th, 2025 - https://www.webmd.com/migraines-headaches/migraine-treatments) describes “therapeutic agent” structure for the purposes of treating headaches and/or migraines.
WebMD discloses, “Drugs for migraine headaches can relieve the pain and symptoms of a migraine attack and help prevent further migraine attacks. Migraines can be treated with two types of drugs: abortive and preventive.”
More specifically, WebMD discloses acute medications for migraines such as ibuprofen, aspirin, acetaminophen, isometheptene-dichloralphenazone-acetaminophen, celecoxib, diclofenac potassium, and indomethacin. As well as triptans and ditans that target serotonin such as: Almotriptan, Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Sumatriptan, and Zolmitriptan; plus the triptans with NSAIDs: Sumatriptan-naproxen and Rizatriptan-meloxicam. Other drugs for acute migraine treatments: CGRP antagonists such as Rimegepant, Ubrogepant, and zavegepant; and Ergots: dihydroergotamine and ergotamine tartrate.
WebMD discloses drugs for migraines lasting 72 hours or more: prednisone, chlorpromazine, droperidol, metoclopramide, and prochlorperazine.
WebMD discloses preventative medication for migraines: (1) medications that treat high blood pressure such as propranolol, timolol, metoprolol, and verapamil; (2) antidepressants such as amitriptyline and nortriptyline; (3) anti-seizure medication such as gabapentin, topiramate, and valproic acid; (4) CGRP inhibitors used to block the calcitonin gene-related peptide such as atogepant, eptinezumab, erenumab, fremanezumab, galcanezumab, Rimegepant, and zavegpant; (5) botox.
Despite Yu et al and WebMD disclosing the structure of one inhibitory nucleic acid molecule and multiple therapeutic agents, respectively, this art does not offset the deficiencies of the envisioned subgenus of inhibitory nucleic acid molecule that hybridizes to an SCN11A mRNA molecule comprising an antisense nucleic acid molecule, siRNA, or shRNA of the specification. Moreover, Yu et al and WebMD, do not disclose that their described species of one antisense oligodeoxynucleotide targeting SCN11A DNA and multiple listed therapeutic agents have the function of treating a subject having a headache or a migraine and decreasing expression of the SCN11A polypeptide in a cell in the subject, in combination.
Therefore, the art does not appear to offset the deficiencies of the specification. Merely describing a “inhibitory nucleic acid molecule that hybridizes to an SCN11A mRNA molecule (e.g., an antisense nucleic acid molecule, siRNA, or shRNA)” and/or “therapeutic agent” capable of treating a subject having a headache or migraine and decreasing expression of the SCN11A polypeptide in a cell in the subject without sufficient detail (e.g., length of the nucleotide, percent complementarity, if there are modifications, and/or defined therapeutic agent(s)) relating to the genera of “inhibitory nucleic acid molecule that hybridizes to an SCN11A mRNA molecule (e.g., an antisense nucleic acid molecule, siRNA, or shRNA)” and/or “therapeutic agent” in treating a subject having a headache or migraine and decreasing expression of the SCN11A polypeptide in a cell in the subject does not allow the skilled artesian to reasonably conclude that the Applicants were in possession of the claimed invention in claim(s) 1, 10-17, and 25-28 .
Response to arguments:
Applicant’s remarks received on 02/27/2026 have been fully considered but they are not persuasive for at least the following reasons.
Applicant contends that by adding the limitation “that hybridizes to a sequence within an SCN11A mRNA molecule” and removing “antibody and small molecule” from claim 1 and 14, overcomes the broad recitation of “the SCN11A inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an SCN11A nucleic acid molecule, a small molecule, or an antibody.” Applicant states that all of the inhibitors recited now have a common and predictable structure, i.e., the nucleotide sequence complementary to the sequence of the SCN11A mRNA molecule.
Despite adding “hybridizes to a sequence within an SCN11A mRNA molecule”, Applicant has not demonstrated possession of a set of nucleic acids that hybridize to a sequence within an SCN11A mRNA. Regarding structure, the claims lack defined nucleotide length, percent complementarity, and whether or not modifications (e.g., sugar, backbone, etc) are incorporated. In regard to defined function, each structural component listed in the previous sentence necessitates a different degree of decreasing (or knocking down) mRNA expression and further decreasing expression of associated polypeptides.
Thus, although the amendment(s) to claim 1 and 14 incorporate the limitations of claims not previously rejected, the rejection is maintained for the reasons presented above.
Claim Rejections - 35 USC § 112 – Enablement
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(s) 1, 10-17, and 25-28 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is a new rejection.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, 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 claims, with the most relevant factors discussed below.
Nature of the invention:
Claim 1 is drawn to a method for treating a subject having a migraine, the method comprising administering a Sodium Voltage-Gated Channel Alpha Subunit 11 (SCN11A) inhibitor to the subject, wherein the SCN11A inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an SCN11A nucleic acid molecule, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA) that hybridizes to a sequence within an SCN11A mRNA molecule and decreases expression of the SCN11A polypeptide in a cell in the subject. The nature of the invention is complex in that the antisense, siRNA, or shRNA that hybridizes to a sequence within an SCN11A mRNA must be capable of treating a subject having a headache or migraine and decreasing expression of the SCN11A polypeptide in a cell in the subject.
Claim 14 is drawn to a method of treating a subject with a therapeutic agent that treats or inhibits a headache or a migraine, wherein the subject has a headache or a migraine by administering a therapeutic agent that prevents a headache or a migraine, the method comprising: determining whether the subject has a Sodium Voltage-Gated Channel Alpha Subunit 11 (SCN11A) predicted loss-of-function variant nucleic acid molecule by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the SCN11A predicted loss-of-function variant nucleic acid molecule; and administering or continuing to administer the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in a standard dosage amount to a subject that is SCN11A reference, and/or administering an SCN11A inhibitor to the subject;
administering or continuing to administer the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in an amount that is the same as or less than a standard dosage amount to a subject that is heterozygous for the SCN11A predicted loss-of-function variant nucleic acid molecule, and/or administering an SCN11A inhibitor to the subject;
or administering or continuing to administer the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in an amount that is the same as or less than a standard dosage amount to a subject that is homozygous for the SCN11A predicted loss-of-function variant nucleic acid molecule;
wherein the SCN11A inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an SCN11A nucleic acid molecule,
wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA) that hybridizes to a sequence within an SCN11A mRNA molecule and decreases expression of the SCN11A polypeptide in a cell in the subject;
and wherein the presence of a genotype having the SCN11A predicted loss-of-function variant nucleic acid molecule indicates the subject has a decreased risk of developing a headache or a migraine.
The nature of the invention is complex in that the therapeutic agent and/or administering an antisense, siRNA, or shRNA that hybridizes to a sequence within an SCN11A mRNA must be capable of treating a subject having a headache or migraine decreasing expression of the SCN11A polypeptide in a cell in the subject by: determining whether a subject has an SCN11A variant nucleic acid molecule (heterozygous, homozygous, or SCN11A reference (“When the subject lacks an SCN11A predicted loss-of-function variant nucleic acid molecule (i.e., the subject is genotypically categorized as SCN11A reference), then the subject has an increased risk of developing a headache or a migraine”, see page 51 of the specification, lines 17-19) and varying the dosages of therapeutic agent (standard, same, or less than standard) depending on which SCN11A variant nucleic acid the subject is determined to have (heterozygous, homozygous, or reference).
Breadth of the claims:
The broadest reasonable interpretation of claim 1 is that the invention is drawn to a method of treating a subject having any/all types of headaches or any/all types of migraines, the method comprising administering any/all antisense, siRNAs, or shRNA targeting any/all positions of the SCN11A mRNA, wherein any/all antisense, siRNAs, or shRNA targeting any/all positions of the SCN11A mRNA are capable of decreasing expression of the SCN11A polypeptide in a cell in the subject. The claims broadly encompass “antisense, siRNAs, or shRNA targeting SCN11A mRNA” defined solely or primarily by function.
The broadest reasonable interpretation of claim 14 is that the invention is drawn to a method of treating a subject with any/all therapeutic agents that treats or prevents any/all types of headaches or any/all types of migraines, wherein the subject has any type of headaches or any type of migraine by administering any/all therapeutic agents that prevents any/all types of headaches or any/all types of migraines, the method comprising: determining whether the subject has any/all Sodium Voltage-Gated Channel Alpha Subunit 11 (SCN11A) predicted loss-of-function variant nucleic acid molecule by: obtaining or having obtained any/all biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has any/all genotype(s) comprising the SCN11A predicted loss-of-function variant nucleic acid molecule; and administering or continuing to administer any therapeutic agent that treats, prevents, or inhibits the headache or the migraine in a standard dosage amount to a subject that is SCN11A reference, and/or administering an SCN11A inhibitor to the subject; administering or continuing to administer the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in an amount that is the same as or less than a standard dosage amount to a subject that is heterozygous for the SCN11A predicted loss-of-function variant nucleic acid molecule, and/or administering an SCN11A inhibitor to the subject; or administering or continuing to administer the therapeutic agent that treats, prevents, or inhibits the headache or the migraine in an amount that is the same as or less than a standard dosage amount to a subject that is homozygous for the SCN11A predicted loss-of-function variant nucleic acid molecule; wherein the SCN11A inhibitor comprises any/all inhibitory nucleic acid molecule that hybridizes to an SCN11A nucleic acid molecule; wherein the inhibitory nucleic acid molecule comprises any/all antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA) that hybridizes to a sequence within an SCN11A mRNA molecule and decreases expression of the SCN11A polypeptide in a cell in the subject; and wherein the presence of a genotype having the SCN11A predicted loss-of-function variant nucleic acid molecule indicates the subject has a decreased risk of developing a headache or a migraine. The claim broadly encompasses “therapeutic agent” and “antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA) that hybridizes to a sequence within an SCN11A mRNA molecule” defined solely or primarily by function.
The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification:
Looking to the specification for guidance on (a) treating headaches or migraines, (b) forms of headaches or migraines, (c) antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA) that hybridizes to a sequence within an SCN11A mRNA molecule, and (d) therapeutic agents.
(a/b) “The terms "treat", "treating", and "treatment" and "prevent", "preventing", and "prevention" as used herein, refer to eliciting the desired biological response, such as a therapeutic and prophylactic effect, respectively. In some embodiments, a therapeutic effect comprises one or more of a decrease/reduction in a headache or a migraine, a decrease/reduction in the severity of a headache or a migraine (such as, for example, a reduction or inhibition of development of a headache or a migraine), a decrease/reduction in symptoms and headache- or migraine-related effects, delaying the onset of symptoms and headache- or migraine-related effects, reducing the severity of symptoms of headache or migraine-related effects, reducing the number of symptoms and headache or migraine related effects, reducing the latency of symptoms and headache- or migraine-related effects, an amelioration of symptoms and headache- or migraine-related effects, reducing secondary symptoms, reducing secondary infections, preventing relapse to a headache or a migraine, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, increasing time to sustained progression, speeding recovery, or increasing efficacy of or decreasing resistance to alternative therapeutics, and/or an increased survival time of the affected host animal, following administration of the agent or composition comprising the agent. A prophylactic effect may comprise a complete or partial avoidance/inhibition or a delay of a headache or a migraine development/progression (such as, for example, a complete or partial avoidance/inhibition or a delay), and an increased survival time of the affected host animal, following administration of a therapeutic protocol. Treatment of a headache or a migraine encompasses the treatment of a subject already diagnosed as having any form of a headache or a migraine at any clinical stage or manifestation, the delay of the onset or evolution or aggravation or deterioration of the symptoms or signs of a headache or a migraine, and/or preventing and/or reducing the severity of a headache or a migraine.”, (see pages 50-51).
(c) A detailed description on the antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA) that hybridizes to a sequence within an SCN11A mRNA molecule can be found above in the “Written Description” section. Of note, the table from page 7 to page 33 lists variant nucleic acid molecules of SCN11A.
(d) A detailed description on the therapeutic agents can be found above in the “Written Description” section.
Existence of working examples:
Example 1 is a Meta analysis of headache and migraine. This data pooled was from four cohorts (UK Biobank, Geisinger, Malmo diet and cancer study, and Mt. Sinai BioMe Biobank). Applicant identified rate, predicted loss-of-function variants for SCN11A associated with protection from headaches and migraines, “suggesting that downregulation or inhibition of SCN11A could protect from headaches and migraines.”, (see page 66).
Although this is a promising field, there are no cellular studies or additional model-approved studies to corroborate the association of SCN11A loss-of-function variant nucleic acids and headaches or migraines.
Predictability and state of the art:
Looking to the art for types of headaches and migraines, American Migraine Foundation (American Migraine Foundation: What Type of Headache Do You Have? Published January 19th, 2023 - https://americanmigrainefoundation.org/resource-library/what-type-of-headache-do-you-have/) discloses eleven different types of headaches and migraines with how they are triggered.
American Migraine Foundation discloses the following: (1) a migraine with aura- lasting 5-60 minutes and can occur with or without a headache; (2) a migraine without aura – accounts for 70-75% of patients, symptoms are moderate to severe head pain with pulsing or throbbing pain on one side of the head, made worse by physical activity; (3) migraine without headache; (4) hemiplegic migraine – which is a rare form of a migraine with weakness on one side of the body, it may be accompanied by aura symptoms or “pins and needles”, can last for several hours to days; (5) retinal migraine – causes temporary vision loss in one eye for 5 to 60 minutes; (6) chronic migraine – impacting 3-5% of the American population, defined by 15 or more days with a headache per month for three or more months, where 8 of those headache days must have migraine symptoms; (7) abdominal migraine – experienced by children and is characterized by a pain located in their middle of the stomach near the belly button, attacks typically last two to 72 hours; (8) migraine “let down” headache, commonly triggered by stress, however relaxing after stressful events can also trigger it; (9) ice pick (or primary stabbing) headache – often come on suddenly with an intense, sharp pain, lasting 5 to 30 seconds but incredibly painful; (10) cluster headache – a disorder characterized by attacks that come in groups, a patient might experience severely painful headache attacks anywhere from one to eight times per day lasting from 15 to 180 minutes; and (11) cervicogenic headache – triggered by an injury or disorder affecting the neck or cervical spine, injuries and arthritis are common causes.
Looking to the art for how to treat migraines and/or headaches, WebMD (Migraine Headache Treatment, Written by WebMD Editorial Contributors, Published January 20th, 2025 - https://www.webmd.com/migraines-headaches/migraine-treatments) discloses migraine headache treatments.
WebMD discloses, “Drugs for migraine headaches can relieve the pain and symptoms of a migraine attack and help prevent further migraine attacks. Migraines can be treated with two types of drugs: abortive and preventive.”
More specifically, WebMD discloses acute medications for migraines such as ibuprofen, aspirin, acetaminophen, isometheptene-dichloralphenazone-acetaminophen, celecoxib, diclofenac potassium, and indomethacin. As well as triptans and ditans that target serotonin such as: Almotriptan, Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Sumatriptan, and Zolmitriptan; plus the triptans with NSAIDs: Sumatriptan-naproxen and Rizatriptan-meloxicam. Other drugs for acute migraine treatments: CGRP antagonists such as Rimegepant, Ubrogepant, and zavegepant; and Ergots: dihydroergotamine and ergotamine tartrate.
WebMD discloses drugs for migraines lasting 72 hours or more: prednisone, chlorpromazine, droperidol, metoclopramide, and prochlorperazine.
WebMD discloses preventative medication for migraines: (1) medications that treat high blood pressure such as propranolol, timolol, metoprolol, and verapamil; (2) antidepressants such as amitriptyline and nortriptyline; (3) anti-seizure medication such as gabapentin, topiramate, and valproic acid; (4) CGRP inhibitors used to block the calcitonin gene-related peptide such as atogepant, eptinezumab, erenumab, fremanezumab, galcanezumab, Rimegepant, and zavegpant; (5) botox.
Looking to the art for targeting Human SCN11A, Clube (US Patent 9139648 B2, published September 22nd, 2015; listed as #1 under U.S. Patents on IDS filed 07/12/2023) discloses methods, compositions, and kits, for targeting variants of Nav1.9.
More specifically, Clube discloses, “A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI), wherein the TOI is present in humans as different polymorphic variants, the method comprising a. Administering to the human an anti-TOI ligand to target a TOI variant in the human and treat or prevent said disease or condition, wherein the TOI in said human is a variant encoded by a nucleotide sequence having a cumulative human allele frequency of more than 50% and/or having a total human genotype frequency of more than 50%; wherein b. Before step (a) said human has been or is genotyped as negative for a variant nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%; or phenotyped as negative for a TOI variant encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%”, (column 2, line 51 to column 3, line 3).
“Optionally in the present invention the TOI is selected from the group consisting of human TOIs: PCSK9, IL6R, IL4Ra, VEGF-A, Placental growth factor (PGF), PDGF-B, PDGFR-B, Ang-2, Nav1.7, Nav1.8, Nav1.9, PD-1, PD-L1, ICOS, BMP6, hemojuvelin, ferroportin, TMPRSS6, transferrin, human hemochromatosis protein (HFE) and sclerostin.”, (column 17, lines 3-7).
“Optionally, the NAV-mediated disease or condition is selected from any one of the following… h. headache pain (such as tension headache, migraine and cluster headache)”, (see column 204, lines 40-41).
Clube discloses in Example 10 antibodies targeting Nav1.9 and tailoring antibodies to target rare Nav1.9 variant profiles (encompassed in columns 533 to 556).
Looking to the art for SCN11A’s involvement in pain Porreca et al (A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain, Proc Natl Acad Sci USA, Volume 96, pages 7640-7644, Published July 1999) and Yu et al (Antisense-Mediated Knockdown of Nav1.8, but not Nav1.9, Generates Inhibitory Effects on Complete Freund’s Adjuvant-Induced Inflammatory Pain in Rat, Plos One, Volume 6, Issue 5, Pages 1-9, Published May 10th, 2011) discloses NaN/Nav1.9 (also known as SCN11A) involvement in pain:
Porreca et al discloses, “In contrast to the findings with PN3 antisense, spinal administration of antisense (5′ GCC TTG TCT TTG GAC TTC TTC 3′) and mismatch (5′ GCT CTG TTC TTG AGC TTT CTC 3′) ODN to NaN/SNS2 failed to produce any change in sensory thresholds after spinal nerve (L5/L6) ligation injury (Fig. 5) and did not alter gross behavior, as demonstrated by normal food intake, weight gain, and/or motor performance, in spite of a significant “knock-down” of the NaN/SNS2 protein (Fig. 6). This observation suggests, therefore, that the NaN/SNS2 subtype of TTX-insensitive sodium channel appears unlikely to play a prominent role in the alterations in the sensory phenotype that have been proposed to contribute to the ongoing paresthesias and pain after peripheral nerve injury.”, (page 7643, column 2, paragraph 3; and see figure 5A-B and figure 6).
“Collectively, therefore, the data suggest that the primary symptoms of neuropathic pain may be significantly attenuated by interfering with the expression and, consequently, the function of PN3 but not of other sodium channels, which are mainly distributed within the DRG such as NaN/SNS2.”, (see page 7644, column 1, paragraph 2).
Yu et al discloses the activation of Nav1.8 and Nav1.9 at the mRNA and protein level with Complete Freund’s Adjuvant (CFA) treatment (see Figure 1A-F). Yu et al discloses successful knock down of NaV1.9 in DRG neurons from naïve and CFA treated rats (see Figure 3 A-C). However, when looking at pain hypersensitivity, only the Nav1.8 antisense reversed the CFA-induced pain, and the Nav1.9 antisense did not (see Figure 4 A-B and Figure 5 A-B).
Yu et al concludes, “First, CFA inflammation treatment caused increased expressions of NaV1.8 and NaV1.9 in primary sensory DRG neurons. Functional analysis on the different components of voltage-gated sodium currents [25,26] demonstrated that CFA treatment significantly increased the sodium current densities of NaV1.8 and NaV1.9, but had no effects on TTX-S sodium currents. Second, intrathecal administration of NaV1.8 and NaV1.9 AS ODN significantly decreased CFA-induced proteins up-regulation and functional enhancement of TTX-R sodium channels. Third, behavioral tests showed that NaV1.8, but not NaV1.9, AS ODN could reverse CFA-induced heat and mechanical hypersensitivity. Our data indicated that the key pain modulators NaV1.8 and NaV1.9 played distinct regulations on the processing of CFA-induced inflammatory pain and that antisense oligodeoxynucleotide-mediated blocking of NaV1.8 over-expression might point toward a potential treatment strategy against certain types of pathological pain.”, (see Discussion, paragraph 1 starting on page 4).
For the oligodeoxynucleotides (AS ODNS), Yu et al discloses, “NaV1.8 and NaV1.9 were previously reported [20] and the sequences were 5’-TCCTCTGTGCTTGGTTCTGGCCT-3’ and 5’- GCCTTGTCTTTGGACTTCTTC-3’, respectively... ”, (The fluorescence labeling of ODNs were carried out by conjugation of carboxy fluorescein (FAM) to the 59 end of the ODNs, and synthesized as phosphodiester ODNs using standard O-cyanoethylphosphoramidite chemistry (Shanghai Sanggon Biological Engineering Technology Services Co., Ltd, China). Intrathecal (i.t.) delivery method was previously described [48] and ODNs (45 mg/5 ml, dissolved in nuclease-free ultrapure water) were i.t. administered twice daily for three consecutive days.”, (see pages 6-7 under Antisense oligodeoxynucleotide delivery).
Lastly, looking to the art on interpreting correlation of a genetic variants versus disease causation, Burgess et al (Inferring Causal Relationships Between Risk Factors and Outcomes from Genome-Wide Association Study Data, Annu Rev Genomics Hum Genet, Vol 19, Pages 303-327, Published August 31st, 2018) teaches reviewing the Mendelian randomization paradigm for making causal inferences using genetic variants.
More specifically Burgess et al teaches, “An observational correlation between a suspected risk factor and an outcome does not necessarily imply that interventions on levels of the risk factor will have a causal impact on the outcome (correlation is not causation). If genetic variants associated with the risk factor are also associated with the outcome, then this increases the plausibility that the risk factor is a causal determinant of the outcome. However, if the genetic variants in the analysis do not have a specific biological link to the risk factor, then causal claims can be spurious.”, (abstract).
The state-of-the-art teaches in American Migraine Federation and WebMD that there are multiple types of migraines and/or headaches that range from acute to chronic, dull to stabbing pain, with and without an aura, as well as children developing stomach migraines. WebMD teaches types of drugs (therapeutic agents) for treatment and prevention ranging from typical over-the-counter medications to serotonin inhibitors to anti-depressants, anti-seizures, and even botox. WebMD also teaches there are Calcitonin gene producing peptide inhibitors, however, WebMD is silent on antisense oligonucleotides, siRNAs, and shRNAs being used for treatments for migraines and/or headaches, however the drugs associated with targeting Calcitonin gene producing peptide inhibitors are small molecules or antibodies. Along the lines of antibody treatments, Clube disclose tailoring Nav1.9 variant antibodies for the treatment/prevention of pain-related diseases or conditions such as headaches and migraines. Porreca et al and Yu et al disclose antisense targeting DNA, not mRNA, as well as once Nav1.9 is targeted, despite a decrease in protein, there is no effect of the antisense oligos on Rat behavior or neuron firing. Moreover, all of the art above is silent on the combination of antisense oligonucleotide and a therapeutic agent for the treatment of headaches or migraines that also decrease SNC11A peptides. Lastly, Burgess et al highlights that correlation is not causation, and even if one has strong indications of a variant(s) relation to a disease/condition, the most that indication will provide is either a reliable or relevant casual inference.
Thus, one of ordinary skill in the art would appreciate the unpredictability of treating a subject having any/all forms of a headache or migraine, by administering any/all antisense nucleic acids, siRNA, and shRNA targeting SCN11A mRNA and/or any/all therapeutic agents; wherein the presence of a genotype having any/all SCN11A variant nucleic acid molecules indicates the subject has a decreased risk of developing a headache or a migraine.
Amount of experimentation necessary:
The quantity of experimentation required to carry out the scope of the invention is large. One would be required to (1) screen random antisense nucleic acids, siRNA, and shRNA targeting random locations on the SCN11A mRNA that cover the various functions of the broad genus of inhibitory nucleic acid molecule that hybridizes to an SCN11A mRNA molecule (e.g., an antisense nucleic acid molecule, siRNA, or shRNA) for the ability to treat headaches or migraines and decrease expression of SCN11A polypeptide in a field-accepted model; (2) screen random therapeutic agents that cover the various functions of the broad genus of therapeutic agents for the ability for treating headaches or migraines and decrease SCN11A polypeptide in combination with a chosen inhibitory nucleic acid molecule that hybridizes to an SCN11A mRNA from the random screen in (1). This type of experimentation is not routine in the art and would require a large amount of inventive effort. Further considering any positive results (e.g., successful treatment of headaches and migraines) would amount to a significant advancement in the state-of-the-art, additional experimentation required is considered undue.
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 and/or use the claimed invention. Therefore, claim(s) 1, 10-17, and 25-28 are not considered to be enabled by the instant disclosure.
Claim Rejections - 35 USC § 102
Response to amendments:
The rejection of claim(s) 1, 3, and 4 under 35 U.S.C. 102(a)(1) as being anticipated by Collard et al (US PGPUB 2013/0096183A1, published April 18th, 2013; Effective filing date of June 23rd, 2011) has been withdrawn in view of the new 35 U.S.C 112(a) – Total lack of enablement rejection above.
Claim Rejections - 35 USC § 103
Response to amendments:
The rejection of claim 19 under 35 U.S.C. 103 as being unpatentable over Collard et al (US PGPUB 2013/0096183A1, published April 18th, 2013; Effective filing date of June 23rd, 2011), Clube et al (US9139648B1; published September 22nd, 2015; Effective filing date of March 23rd, 2015), Liang (Molecular Pain 9:31, 2013), and Zhang et al (Amer.J Human Genet., 93, 2013), is moot in view of Applicant’s cancellation of the claims in the reply filed 02/27/2026.
The rejection of claim(s) 10-17 and 25-28 under 35 U.S.C. 103 as being unpatentable over Collard et al (US PGPUB 2013/0096183A1, published April 18th, 2013; Effective filing date of June 23rd, 2011), Clube et al (US9139648B1; published September 22nd, 2015; Effective filing date of March 23rd, 2015), Liang et al (Molecular Pain 9:31, 2013), and Zhang et al (Amer.J Human Genet., 93, 2013) has been withdrawn in view of Applicant’s amendments to the claims filed 02/27/2026. This rejection has been withdrawn in view of the new 35 U.S.C 112(a) – Total lack of enablement rejection as seen above.
Conclusion
No claims allowed.
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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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