DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s Amendment
1) Acknowledgment is made of Applicant’s amendment filed 11/04/2025 in response to the non-final Office Action mailed 06/04/25. Said amendment is non-compliant under 37 CFR 1.121 in that the claims previously withdrawn as being directed to a non-elected species have incorrect status identifiers.
Status of Claims
2) Claims 8, 18 and 19 have been amended via the amendment filed 11/04/25.
Claims 1-20 are pending.
Claims 1, 3, 7-12, 15 and 18-20 are examined on the merits.
Prior Citation of Title 35 Sections
3) The text of those sections of Title 35 U.S. Code not included in this action can be found in a prior Office Action.
Prior Citation of References
4) The references cited or used as prior art in support of one or more rejections in the instant Office Action and not included on an attached form PTO-892 or form PTO-1449 have been previously cited and made of record.
Rejection(s) Withdrawn
5) The rejection of claim 20 set forth at paragraph 11(a) of the Office Action mailed 06/04/25 under 35 U.S.C § 112(b) or 35 U.S.C § 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s amendment to claim 19.
6) The rejection of claim 8 set forth at paragraph 11(c) of the Office Action mailed 06/04/25 under 35 U.S.C § 112(b) or 35 U.S.C § 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s claim amendment.
7) The rejection of claim 18 set forth at paragraph 11(d) of the Office Action mailed 06/04/25 under 35 U.S.C § 112(b) or 35 U.S.C § 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s claim amendment.
Rejection(s) Maintained
8) The rejection of claims 1, 3, 7-12, 15 and 18-20 set forth at paragraph 9 of the Office Action mailed 06/04/25 on the ground of non-statutory double patenting as being unpatentable over claims 1, 3, 7-11, 13 and 17-19 U.S. Patent No. 11,090,371 B1 (of record), is maintained.
Applicant states the following:
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However, no terminal disclaimer has been filed in this application along with Applicant’s amendment and Remarks filed 11/04/25 or as of the issuance of this Office Action.
Rejection under 35 U.S.C § 112(b) or (Pre-AIA ) Second Paragraph Maintained
9) The rejection of claim 7 set forth at paragraph 11(b) of the Office Action mailed 06/04/25 under 35 U.S.C § 112(b) or 35 U.S.C § 112 (pre-AIA ), second paragraph, as being indefinite is maintained.
Applicant refers to spec [0060] and states that it discusses "fragments of botulinum neurotoxins," giving concrete structural examples (e.g., a fragment comprising the proteolytic domain of the toxin and/or a translocation domain, and fragments that lack a functional targeting moiety) explaining how such fragments can exert their effects within the cell. Applicant states that the same passage teaches an optional co-administration with a local pH-lowering composition to facilitate translocation across cell membranes, further tying structure to function. Applicant asserts that this disclosure provides exactly the structure-function correlation the case law Ariad Pharms. v. Eli Lilly, 598 F.3d 1336, 1350-56 (Fed. Cir. 2010) and Enzo Biochem v. Gen-Probe, 323 F.3d 956, 964-68) require. Applicant states that read together with the specification's micro-dose, intradermal/subcutaneous delivery to dermatomes to normalize Substance P/CGRP, the claims use fragment in a way that is both technically precise and fully enabled. With these, Applicant opines that a POSITA would understand the metes and bounds of "fragment" in this therapeutic context.
Applicant’s arguments have been carefully considered, but are not persuasive. First, there is no “spec [0060]” in the as-filed application. Second, the instant rejection is of indefiniteness under 35 U.S.C § 112(b) and not of enablement or structure-function correlation under 35 U.S.C § 112(a). The instant indefiniteness rejection applies to ‘a fragment thereof’ in the dependent claim 7, which as presented is drawn to:
The method of claim 1, wherein the botulinum toxin comprises botulinum toxin type A ........., a fragment thereof .....
Thus, the recited ‘a fragment thereof’ is a fragment of the botulinum toxin comprising botulinum toxin A therein, i.e., a fragment of the botulinum toxin of broader scope comprising within it botulinum toxin type A (the elected species) of narrower scope. It is unclear whether or not the recited and undefined ‘a fragment thereof’ is of ‘the botulinum toxin’ of broader scope, or is it ‘a fragment’ of the ‘botulinum toxin type A’ of narrower scope that is comprised within ‘the botulinum toxin’ of broader scope, or a portion from both botulinum toxins. As set forth previously, the claim fails to distinctly claim the subject matter by providing adequate structure allowing one to identify precisely that which is being claimed. The precise structural boundaries of the recited ‘a fragment thereof’ are unclear and therefore the metes and bounds of the claim are indeterminate.
Rejection under 35 U.S.C § 112(a) or (Pre-AIA ), First Paragraph Maintained
10) The following is a quotation 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 35 U.S.C. § 112 (pre-AIA ), first paragraph:
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 the invention.
11) The rejection of claims 1, 3, 7-12, 15 and 18-20 set forth at paragraph 13 of the Office Action mailed 06/04/25 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 requirements is maintained.
Applicant submits the following arguments (see page 8):
3. Enablement - no undue experimentation
Applying the Wands factors, In re Wands, 858 F.2d 731 (Fed. Cir. 1988): the specification i) provides precise dose (1-4 units), ii) exact route/site (intradermal/subcutaneous to a dermatome at trigeminal and paraspinal vicinities), iii) mechanistic guidance (C-fiber access; Substance P/CGRP normalization), and iv) worked micro-dose examples within the claimed range. Given that level of guidance, any routine clinical titration is not undue. It is respectfully submitted that the same reasoning was advanced in the related application 17/987,675, which is now patented as US 11090371.
Applicant refers to MPEP 2163.02; 2163.06(ii)(B) and contends that the specification’s 1-150 units range ([0061]) plus explicit 2-4 units examples and a detailed route/site rationale together convey possession of the 1-4 units sub-range at filing. Applicant states that the disclosure ties intradermal/subcutaneous, dermatome-based delivery around trigeminal and paraspinal nerves to access unmyelinated C-fibers and normalize Substance P/CGRP - the therapeutic endpoint for cirrhosis-related symptomatology and that structure-function teaching removes guesswork and distinguishes this regimen form [sic] unrelated intramuscular contexts emphasized in US 8,747,865B2 cited in the Action (which understandably show does [sic] variability unrelated to the present route/targets). Applicant asserts that even if '865 observes variable outcomes in intramuscular contexts, that observation does not speak to the predictability of the claimed intradermal or subcutaneous micro-dose approach. Applicant submits that even in "unpredictable arts", written description is satisfied where the technology sought to be patented is defined with sufficient functional clarity and the spec demonstrates possession of the claimed invention. Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005); Ariad, 598 F.3d at 1351- 55. Applicant states that here the spec pinpoints agent (BoNT/A or fragment), route/site (intradermal subcutaneous to a dermatome at trigeminal/paraspinal vicinities), and dose (1-4 units), and ties them to a measured physiologic effect (Substance P/CGRP normalization).
Applicant states that fragment species are adequately described. It is stated that spec [0060] identifies concrete fragment types (proteolytic/translocation domains; fragments lacking targeting moieties) and explains their intracellular action, optionally enhanced by local-pH reducing co-administration. Applicant submits that this is a representative disclosure with structure-function correlation sufficient under Ariad and Enzo - enumerating every conceivable fragment is unnecessary. Applicant refers also to [0062] (composition embodiments) and [0061] (dose operability across toxin variants). With these, Applicant states that the claims satisfy written description for "botulinum toxin... or a fragment thereof” used in the specific micro-dose regimen.
Applicant’s arguments have been carefully considered, but are not persuasive.
First, Applicant’s remarks on ‘enablement’, ‘no undue experimentation’, and ‘the Wands factors’ (see page 8) are not understood, since the rejection of record is a written description rejection. Further, the asserted “same reasoning ... advanced in the related application 17/987,675” makes no sense since 17/987,675 is in fact the instant application and it is not yet patented.
Second, there are no “spec [0060]” and “[0062]” in the as-filed application. The dependent claim 7, which as presented is drawn to:
The method of claim 1, wherein the botulinum toxin comprises botulinum toxin type A ........., a fragment thereof .....
The recited ‘the botulinum toxin’ genus broadly encompasses any of many structurally and pharmacologically divergent botulinum toxin types. Thus, the recited ‘a fragment thereof’ is a fragment of the botulinum toxin comprising botulinum toxin A therein, i.e., a fragment of the botulinum toxin of broader scope comprising within it botulinum toxin type A (the elected species) of narrower scope. Thus, ‘a fragment thereof’ encompasses undefined fragment species of ‘the botulinum toxin’ of broader scope and undefined fragment species of the ‘botulinum toxin type A’ of narrower scope and a portion from each of the botulinum toxins. Page 23 of the as-filed specification provides a non-limiting description of a ‘fragment’ comprising the proteolytic domain of the toxin and/or a translocation domain, and fragments that lack a functional targeting moiety) and such fragments that can exert their effects within the cell. However, ‘a fragment’ as recited in claim 7 or as encompassed within the scope of instant claims is not limited to these non-limiting fragment species; instead, it encompasses a huge genus of fragments of the botulinum toxin of broader scope comprising therein botulinum toxin type A of narrower scope, all of divergent structure, length and/or size from any of many structurally divergent botulinum toxin species.
The independent claim 1 includes the limitation “and/or”. Accordingly, the method as claimed, for example in the base claim 1, comprises injecting by subcutaneous or intradermal route, to a patient in need, a minimum of 1 unit of any botulinum toxin or a generic fragment thereof, to or around the vicinity of a cervical nerve, the elected species. While the patient’s neuroexcitatory substances in the method of claim 9 comprise substance P, and the level of the patients’ neuroexcitatory substances in the method of claim 12 is blood level, the patient’s neuroexcitatory substances and the level thereof in the method of rest of the claims currently being examined, are not limited to the neuroexcitatory substance P and not only to the blood level of the genus of neuroexcitatory substances of the patient. Per claim 9, the dosage of the generic botulinum toxin for an adult weighing about 150 lbs is “about 1” unit. Per the definition of “about” within the as-filed specification, about “1 unit” of any botulinum toxin or about “1 unit” of any generic fragment thereof is 0.9 unit. Accordingly, said administration of 0.9 unit to or around the vicinity a cervical nerve lateral to the patient’s spine in an adult weighing about 150 lbs is required to treat cirrhosis in said patient with normalization of the level of patient’s generic neuroexcitatory substances or of the patient’s neuroexcitatory Substance P. Likewise, said administration of 1 unit to a cervical nerve in an adult of no specific weight is required to treat cirrhosis in said patient with normalization of the level of patient’s generic neuroexcitatory substances or of the patient’s neuroexcitatory Substance P. Furthermore, while the patient’s neuroexcitatory substances in the method of claim 9 comprise substance P, and the level of the patients’ neuroexcitatory substances in the method of claim 12 is blood level, the patient’s neuroexcitatory substances and the level thereof in the method of rest of the claims currently being examined, are not limited to the neuroexcitatory substance P and not only to the blood level of the genus of neuroexcitatory substances of the patient. Accordingly, the 0.9 unit or 1 unit of any generic botulinum toxin or the elected type A botulinum toxin species, or any generic fragment thereof of variable structure and/or length/size, upon injection to an adult patient in need as claimed is required to treat cirrhosis in said patient and normalize blood or non-blood level of any generic neuroexcitatory substances or of substance P. However, Applicant was not in possession of a method of such a broad scope at the time of the invention. This is important because as set forth previously, the as-filed specification identifies the various botulinum toxins as having ‘different mechanisms and cleavage sites’ and having ‘different’ potency, dosage, or duration depending on the “type” of botulinum toxin. Additionally, Trizna Z (Dermatologic Use of Botulinum Toxin. Medscape, pages 1-10, 06 Feb 2019, of record) taught that the different types of botulinum toxin are serologically distinct and have different molecular sizes, different degrees of activation, and different mechanisms of action. See page 1 of Trizna Z. Trizna Z further taught that the various commercial preparations have different characteristics regarding their clinical performance. See page 1 of Trizna Z. The elected botulinum toxin species is type A botulinum toxin or a fragment thereof. Just within type A botulinum toxin preparations alone, the art discloses the existence of different varieties of BoNT/A formulations such as Onabotulinumtoxin-A (ABO-BoNT/A), Incobotulinumtoxin-A (INCO-BoNT/A), Abobotulinumtoxin-A (ABO-BoNT/A), Xeomin etc and recognizes the pharmacological and immunological differences as well as major structural or compositional differences among them, i.e., BoNT/A formulations containing and not containing complexing proteins. See entire document entitled Understanding Different Types of Botulinum Toxin A, Harley Academy, pages 1-5, 09 July 2021 (of record). Thus, the broad botulinum toxin genus encompasses various art-known type A botulinum toxin formulations exemplified supra as well as botulinum toxin fragment species of variable length/size, structure and/or functions. Furthermore, as known in the art, the generic term ‘botulinum toxin’ and the elected type A botulinum toxin species broadly encompass wild-type or native sequences as well as variants, mutants, and fragments thereof having x% sequence identity thereto with amino acid substitutions, deletions, additions, and/or insertions. For example, see sections [0388], [0436], [0441] and [0030] of US 20200239528 A1 (of record). The claimed method of administering 0.9 unit or 1 unit of said botulinum toxin species or fragment species thereof as claimed is required to treat cirrhosis. The term ‘cirrhosis’ encompasses within its scope alcoholic liver cirrhosis, nonalcoholic cirrhosis, cryptogenic cirrhosis, primary biliary cirrhosis, secondary biliary cirrhosis etc. See page 2 of Alivia Nyhan. Types of cirrhosis and their causes, pages 1-9, 21 August 2021 (of record). The claimed method further includes the step of monitoring if the patient’s blood or non-blood level of generic neuroexcitatory substances or of Substance P normalizes. The art recognizes that an elevated blood level of neuroexcitatory substance P is not limited to cirrhosis patients, but is also found in other conditions or diseases such as patients with sickle cell disease (see Michaels et al. Blood 92: 3148-3151, 1998, of record) and moderately emetogenic chemotherapy-induced nausea and vomiting (see Park et al. Cancer Medicine 10: 1057-1065, 2021, of record). As set forth previously, a review of the instant application indicates that, at the time of the invention, Applicant was not in possession of the method of treating cirrhosis by injecting intradermally or subcutaneously, for example, 0.9 unit or 1 unit of the genus of botulinum toxin and the genus of the fragments as claimed. Given the unpredictability associated with a specific route of administration of a botulinum toxin to elicit therapeutically impressive results in human patients as taught by US patent 8747865 B2 (of record), a skilled artisan would look into Applicant’s as-filed specification to see whether Applicant was in possession of a method of treating cirrhosis as claimed by injecting intradermally or subcutaneously, for example, 0.9 unit or 1 unit of structurally and pharmacologically divergent members of the botulinum toxin genus and the genus of their structurally divergent fragments as claimed. However, such a show of possession at the time of the invention is lacking in the instant application. There is no predictability that said unit of any generic botulinum toxin type or an undefined fragment thereof, injected into or around the vicinity of a cervical nerve lateral to the patient’s spine would be capable of treating any type of cirrhosis in an adult patient in need thereof weighing or not weighing about 150 lbs and normalizing blood or non-blood level of generic neuroexcitatory substances or of neuroexcitatory Substance P. As set forth previously, in the instant case, there is neither any evidence of actual reduction to practice of the full scope of the claimed method, nor has it been shown that the invention is ready for patenting. The therapeutic effect on alcoholic liver cirrhosis, nonalcoholic cirrhosis, cryptogenic cirrhosis, primary biliary cirrhosis, secondary biliary cirrhosis etc of any administered botulinum toxin type species at the recited units including 1 unit or 0.9 unit in a human or non-human patient has not been tested in the instant specification. The therapeutic effect of any botulinum toxin type species injected via a cervical nerve at a unit dose 1 or 0.9 has not been correlated with cirrhosis-treating function in the instant case, nor was it predictable since obtaining similar therapeutic effects with any botulinum toxin type species or it’s fragment species that are structurally, pharmacologically, and immunogenically/ immunologically distinct from one another via any local nerve route including a cervical nerve is an unpredictable event. Clearly, a convincing structure-function relationship is lacking. Applicant has not described the invention of the instant claims sufficiently to show that he/she had possession of the variant genus having the requisite cirrhosis-treating therapeutic function(s) and the full scope of the method as claimed at the time of the invention. The rejection stands.
Conclusion
12) No claims are allowed.
13) THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 C.F.R 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 C.F.R 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
14) Any inquiry concerning this communication or earlier communications from the Examiner should be directed to S. Devi, Ph.D., whose telephone number is (571) 272-0854. A message may be left on the Examiner’s voice mail system. The Examiner is on a flexible work schedule, however she can normally be reached Monday to Friday from 8.00 a.m. to 4.00 p.m. (EST). If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's Supervisor, Daniel E. Kolker, can be reached at (571) 272-3181. The fax phone number for the organization where this application or proceeding is assigned (571) 273-8300.
15) Information regarding the status of an application may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center or Private PAIR to authorized users only. Should you have questions about access to Patent Center or the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). 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.
/S. DEVI/
S. Devi, Ph.D.Primary Examiner
Art Unit 1645
February, 2026