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 .1
Status of Claims
Claims 1-11, 15, 51, 67 and 74-82 are pending.
Election/Restrictions
Applicant’s election of Group I, the chemical specie XEN11012
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and hyperkalemic periodic paralysis in the reply filed on March 4, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon search and examination of the claims, the examined species has been expanded to include the potassium channel opener, retigabine and skeletal muscle disorders, hypokalemic periodic paralysis (HypoPP), Andersen Tawil syndrome (ATS), and thyrotoxic periodic paralysis (TPP).
Note, relevant state of the art references, include Chanchykov et al. Efficacy of a K+ Channel Agonist, XEN1101, For Preserving Contractility in Mouse Models of Hypokalemic Periodic Paralysis, Muscle & Nerve Vol. 73, Issue 4 April 2026 P. 668-674 and Quiñonez et al., Retigabine suppresses loss of force in mouse models of hypokalaemic periodic paralysis, Brain, Volume 146, Issue 4, April 2023, Pages 1554–1560. These references are post-priority date of the examined application. While the claims have been rejected as detailed below, the suggestion to limit the claims to examined species of potassium channel openers and skeletal muscle disorders, as supported by the specification’s working examples and any experimental data in vitro or preferably in vivo will possibly further prosecution of the case to an allowance.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 20 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112 - Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 8, 9, 81 and 82 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.
The indefinite claims recite various individual compounds (Kv7 channel openers for claims 8 and 81) and carbonic anhydrase inhibitors for claim 82, and recite the indefinite term “or an analogue of any of the foregoing.”
The specification provides a definition of analogues of retigabine, where it notes non-limiting examples of retigabine analogues are described in Ostacolo et al. See paragraph 67, referencing Ostacolo et al., J Med Chem 2020, 63, 1, 163-185 (cited in the IDS).
Except for retigabine, the term analogue is not defined in the specification for the other Kv7 channel openers or carbonic anhydrase inhibitors.
The common understood definition of analog (or analogue) as a noun is “a . . . thing seen as comparable to another.” 3
This generic common usage of term analog (or analogue) as recited in the claims cannot possibly define the various chemical compounds claimed and is therefore indefinite. The claims indefinitely recite analogues, i.e. compounds with either “comparable” chemical structures and/or chemical activity, which cannot particularly point or distinctly claimed the invention given comparable is a relative term as any two chemical compounds may be compared. See MPEP 2173.05(b).
Claim 9 depends from claim 1 and recites “the effective amount” is said to comprise “administering the potassium channel opener from between about 30 minutes prior to consuming food until 12 hours after consuming food.” Claim 9 is indefinite as an effective amount cannot be said to comprise administration of itself at certain claimed time periods. The effective amount is a dose to be administered, rather than the actual administration step at the time claimed in claim 9. Amendment of claim 9 to recite “wherein the effective amount of the potassium channel opener is administered from between 30 minutes. . . .” will overcome this rejection.
Suggested claim 9 amendment:
9. (Currently amended) The method of claim 1 wherein the effective amount of the potassium channel opener is administered from between about 30 minutes prior to consuming food until 12 hours after consuming food.
Claim Rejections - 35 USC § 112 - Scope of 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.
Claims 1-11, 15, 51, 67 and 74-82 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 treatment of skeletal muscle diseases such as hypokalemic periodic paralysis (HypoPP), hyperkalemic periodic paralysis (HyperPP), and Andersen Tawil syndrome (ATS) with retigabine and/or XEN1101, it does not reasonably provide enablement for the full scope of preventing or treating ANY skeletal muscle disease in a subject with ANY potassium channel opener. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Claim 1 recites it is a” method of preventing or treating a skeletal muscle disease in a subject comprising administering to the subject an effective amount of a potassium channel opener.”
Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth 8 factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
The predictability or unpredictability of the art: The instant claimed invention is highly unpredictable since a person having ordinary skill in the art (PHOSITA) recognizes the broad scope of skeletal muscle disease include conditions such as thyrotoxic period paralysis (TPP) as well Duchenne muscular dystrophy.
Iqbal4 teaches thyrotoxic period paralysis (TPP) presents with muscle weakness, where the patients are afflicted with hypokalemia and hyperthyroidism. See Abstract. Note that Iqbal teaches the state of the art of treating TPP involves potassium replacement (IV therapy), non-selective beta blocker (propranolol), surgery (thyroidectomy), radioactive ablation or anti-thyroid medications (methimazole or propylthiouracil). See Conclusions section, page 3 of 3. While Iqbal teaches the role of potassium ion channels with TPP associated hypokalemia, the fact that potassium channel openers were known at the time of Iqbal, it cannot be said that the full scope of potassium channel opener drugs were enabled to treat TPP, let alone the full scope of skeletal muscle diseases as claimed.
Further, Falzarano5 et al. discloses that Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular inherited neuromuscular disorder due to mutations in the dystrophin gene. . . characterized by progressive muscle weakness and wasting due to the absence of dystrophin protein that causes degeneration of skeletal and cardiac muscle. See Abstract. Falzarano discloses
At this time, [2015] there are no effective treatments and the steroids are the only fully approved drugs used in DMD therapy able to slow disease progression. In the last years, an increasing variety of strategies have been studied as a possible therapeutic approach aimed to restore dystrophin production and to preserve muscle mass, ameliorating the DMD phenotype. RNA is the most studied target for the development of clinical strategies and Antisense Oligonucleotides (AONs) are the most used molecules for RNA modulation. The identification of delivery system to enhance the efficacy and to reduce the toxicity of AON is the main purpose in this area and nanomaterials are a very promising model as DNA/RNA molecules vectors. See Abstract.
At the time of Falzarano in 2015, while potassium channel opener compounds were known, Falzarano notes there are no known treatments of MDD, other than steroids to slow down disease progress and potential RNA strategies. See above. Accordingly, it cannot be said that potassium channel opener drugs were enabled to treat MDD, let alone the full scope of skeletal muscle diseases as claimed.
Therefore, the unpredictability of treating all skeletal muscular diseases with any potassium channel opener as noted by the art is a Wands factor against the enablement of the full scope of the invention.
The breadth of the claims The instant claims are deemed very broad since these claims read on treatment or prevention of any skeletal muscle disease with any potassium channel opener. The broad scope is a Wands factors weighing against enablement of the full scope of the invention.
The amount of direction or guidance presented, and the presence or absence of working examples: It has been established that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” In re Fisher, 427 F.2d 833, 839 166 USPQ 18, 24 (CCPA 1970).
It is pointed out that there are no working examples of in vivo treatment of skeletal muscular diseases with a potassium channel opener as claimed.
Applicant’s working examples are noted to take place in vitro in the soleus muscle from the Nav l.4-R669H mouse and EDL muscle from Cavl.lR528H mouse. See paragraph 32 and Figures 4A-4B, where a specific potassium channel opener, retigabine, induced rescue from loss of force (i.e. paralysis) when compared with the control muscle’s response and a recovery relative peak forced compared to control.
Figures 5A-B, 6, 7 and 8 note the prevention of depolarization of HypoPP fibers during a low potassium challenge by retigabine and also the protective effect of retigabine being prevented by the Kv7 channel inhibitor XE9991; retigabine prevents muscle loss in a pharmacological model of Andersen-Tawil Syndrome and retigabine is ONLY PARTIALLY effective in preventing loss of muscle force in a mouse HyperPP model. See paragraphs 33-35.
Figure 9 discloses that elected species XEN1101 provides protection from the loss of force in a NaV1.4-R669H mouse model of HypoPP.
As the above experimental examples are specifically limited to retigabine to only treat Andersen-Tawil Syndrome, HypoPP and XEN11011; and XEN1101 to provide protection from force loss in a mouse model of HypoPP, the absence of experimental examples to support the full scope of preventing and treating ALL skeletal muscle diseases with ALL potassium channel openers is a Wands factor against the scope of enablement of the full scope of the invention.
Therefore, in view of the Wands factors as discussed above, the state of the art, the broad scope of the invention and lack of amount of direction or guidance presented, Applicant fails to provide information sufficient to practice the claimed invention as broadly as claimed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-8, 10 and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated Dupont et al. Treatment of myotonia congenita with retigabine in mice Experimental Neurology Volume 315, May 2019, Pages 52-59. Dupont is disclosed on the PTO-892 form.
Regarding claims 1-3 and 6-8 and the aspect of the treatment of a skeletal muscle disease by administering to the subject an effective amount of a potassium channel opener, Dupont et al. teaches the treatment of a skeletal muscle disease (myotonia congenita) with a known KCNQ Kv7 potassium channel opener, retigabine in a mouse subject. See title and abstract. Dupont teaches myotonia congenita is a skeletal (sporadic per claim 2, periodic per claim 3) disease where patients suffer from muscle stiffness caused by muscle hyperexcitability. See abstract. Dupont reduced the severity of myotonia in vivo, as measure using a muscle force transducer. See abstract. The nature of myotonia (inability to relax muscle after contraction) occurring during muscle hyperexcitability teaches the claims 2 and 3’s limitations of sporadic and periodic paralysis.
Further note, with regard to the prevention aspect of claims 1-8, as Dupont teaches the administration of potassium channel opener to a subject, such prevention property is taught by Dupont, as it is inherently present in the prior art where Dupont teaches administration of retigabine to a subject, and where all subjects are in need of prevention of a skeletal muscle disease, including those listed in claims 3-5, while not explicitly taught by Dupont, would be inherently prevented by the administration of retigabine.
Regarding claim 10 and the limitation of an abortive therapy (i.e. stops the symptoms of disease), Dupont teaches reduction of myotonia in a subject. Abstract.
Regarding claim 11 and wherein the abortive therapy is achieved with a single dose of potassium channel opener, Dupont teaches reductions in myotonia at doses of 10 and 20 µM of retigabine. See Figure 1 on page 54.
Claims 1-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang & Krauss XEN1101: A Novel Potassium Channel Modulator for the Potential Treatment of Focal Epilepsy in Adults, touchREVIEWS in Neurology. 2022;18(1):2–4.
Wang & Krauss is cited on the PTO-892 form.
This anticipation rejection over Wang and Krauss is directed solely to the prevention aspect of the claims ONLY.
Regarding claims 1-8 and the prevention aspect of the claimed skeletal muscle diseases, such as HypoPP, HyperPP, Andersen Tawil syndrome (ATS), or thyroid period paralysis, Wang & Krauss teach the administration of the potassium channel opener compound XEN1101. See page 3, columns 1-2, disclosing the Phase IIb study of the efficacy and safety of XEN1101 in adult subjects. While not explicitly teaching the prevention of the claimed skeletal muscle diseases, as all subjects are in need of prevention of a skeletal muscle disease, the administration of the potassium channel opener, XEN1101, Wang & Krauss inherently anticipates the prevention of the claimed skeletal muscle diseases.
Claim Rejections - 35 USC § 103
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.
Claims 1-8, 10, 11, 15, 51, 67, 74-76, and 79-82 are rejected under 35 U.S.C. 103 as being unpatentable over Dupont et al. Treatment of myotonia congenita with retigabine in mice Experimental Neurology Volume 315, May 2019, Pages 52-59 in view of Tricarico et al. Carbonic anhydrase inhibitors ameliorate the symptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+channels, Neuromuscular Disorders Volume 16 Issue 1, January 2006 Pages 39-45.
Dupont and Tricarico are disclosed on the PTO-892 form.
Regarding claims 1-3, 6-8, 15 and 51 and the aspect of the treatment of a skeletal muscle disease by administering to the subject an effective amount of a potassium channel opener, Dupont et al. teaches the treatment of a skeletal muscle disease (myotonia congenita) with a known KCNQ Kv7 potassium channel opener, retigabine in a mouse subject. See title and abstract. Dupont teaches myotonia congenita is a skeletal (sporadic per claim 2, periodic per claim 3) disease where patients suffer from muscle stiffness caused by muscle hyperexcitability. See abstract. The nature of myotonia congenita occurring during muscle hyperexcitability teaches the limitations of sporadic and periodic paralysis as claimed. Dupont reduced the severity of myotonia in vivo, as measure using a muscle force transducer. See abstract.
It is noted however, that Dupont does not teach the particular species of claim 1 (not specifically recited) and specifically recited in claims 15, 51, 74-76 and 79-82, where the potassium channel opener is combined with a carbonic anhydrase inhibitor such as acetazolamide, ACTZ.
Tricarico teaches ACTZ resolves the episodic paralysis and transient weakness associated of myotonia (paramyotonia) congenita. See page 39 column 2.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of Dupont to treat a skeletal muscle disease (myotonia congenita) with retigabine (K-channel opener) in combination with the carbonic anhydrase inhibitor, acetazolamide, ACTZ based on the teachings of reference Tricarico (e.g. MPEP 2143 I.(A).6 Both Dupont and Tricarico teach treatment of myotonia with retigabine and ACT, so therefore a prima facie case of obviousness exists per MPEP 2144.06 I., combining equivalents known for the same purpose.7
With regard to the prevention aspect of the rejected claims (1-8, 10, 11, 15, 51, 67, 74-76, and 79-82) as being obvious, as Dupont and Tricarico teach the administration of potassium channel opener and/or a carbonic anhydrase inhibitor to a subject, such prevention property is taught by Dupont, as it is inherently present in the prior art where Dupont teaches administration of retigabine and/or ACTZ to a subject, and where all subjects are in need of prevention of a skeletal muscle disease, such as myotonia congenita, as well as those claimed, such as inherited/sporadic/periodic paralysis and HypoPP, HyperPP, TPP (caused by endogenous or exogenous thyroid) and ATS (per claims 2-5).
Regarding claim 10 and the limitation of an abortive therapy (i.e. stops the symptoms and disease), Dupont teaches the reduction myotonia congenita in a subject. See abstract.
Regarding claim 11 and wherein the abortive therapy is achieved with a single dose of potassium channel opener, Dupont teaches reductions in myotonia at doses of 10 and 20 µM of retigabine. See Figure 1 on page 54.
As detailed above with regard to claims 15 and 51, the teachings of Dupont and Tricarico disclose the combination of a potassium channel opener (retigabine) and carbonic anhydrase inhibitor (ACTZ) to treat the skeletal muscle disease, myotonia congenita, as detailed above.
Regarding claim 67 and the limitation of a sodium channel blocker, Dupont suggests the use of sodium channel blockers such as mexiletine has been used to treat myotonia congenita. See page 52, column 1.
Regarding claim 74 and synergistic therapeutic combination, where both Dupont and Tricarico teach the claimed combination of retigabine and ACTZ (see above), such combination would inherently possess the property of synergism.
Regarding claims 75-76 and the limitations of a sporadic skeletal muscle disease with periodic paralysis, both Dupont and Tricarico teach the claimed combination of retigabine and ACTZ to treat myotonia congenita, see above.
Regarding claims 79-81 and the limitations of Kv7 channel opener (KCNQ2/3 or other listed therein) such as retigabine, Dupont et al. teaches the treatment of a skeletal muscle disease (myotonia congenita) with a known KCNQ Kv7 channel opener, retigabine in a mouse subject. See title and abstract.
Regarding claim 82 and its limitation of ACTZ, Tricarico teaches the carbonic anhydrase inhibitor acetazolamide (ACTZ). See title, abstract and page 39 column 2.
Conclusion and Correspondence
In conclusion, no claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. Examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 CONTINUING DATA This application has PRO 63/418,859 10/24/2022
2 Applicant selects XEN1101, chemical name N-[ 4-( 6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide (see, for example, paragraph [0069] of the specification)
CAS Number: 1009344-33-5
1OP-2198
1OP2198
[4-(6-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide
Azetukalner
Encukalner
VRX621698
N-[4-(6-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide
3 https://www.google.com/search?q=definition+of+analog
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4 Iqbal et al. A Literature Review on Thyrotoxic Periodic Paralysis (August 29, 2020). Cureus 12(8): e10108. DOI 10.7759/cureus.10108
5 Falzarano et al. Duchenne Muscular Dystrophy: From Diagnosis to Therapy Molecules 2015, 20(10), 18168-18184
6 MPEP 2143 I. EXAMPLES OF RATIONALES Examples of rationales that may support a conclusion of obviousness include (A) Combining prior art elements according to known methods to yield predictable results
7 MPEP 2144.06 Art Recognized Equivalence for the Same Purpose [R-01.2024]
I. COMBINING EQUIVALENTS KNOWN FOR THE SAME PURPOSE
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted)
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