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 .
DETAILED ACTION
Applicant's amendments and remarks filed on January 7, 2026 are acknowledged. Claims 2-4, 8-12, 15-17, 21-54, and 56-73 have been canceled. Claims 1, 5, 6, 7, 13, 14, 18, 20, and 55 were amended. Claims 1, 5-7, 13, 14, 18-20, 55, and 74-81 are pending and are examined on the merits herein.
Priority
This application is a continuation of PCT/US2020/048509 filed on August 28, 2020 which claims priority to U.S. provisional application 63/044,163, filed on June 25, 2020, U.S. provisional application 62/925,623 filed on October 24, 2019, and U.S. provisional application 62/894,237 filed on August 30, 2019.
Withdrawn Objections
In view of Applicant’s amendments and response, the claim objections and the objections to the drawings are withdrawn.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(b), 35 U.S.C 112(a) new matter, and 35 U.S.C 101 rejections are withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 7, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings were received on January 7, 2026. These drawings are found acceptable by the examiner.
Specification
The substitute specification filed on January 7, 2026 has been entered. However, the abstract filed on January 7, 2026 has not been entered. It is noted that the amendment to the abstract filed on January 7, 2026 does not comply with the requirements of 37 CFR 1.121(b) because all amendments are not shown with markings relative to the immediate prior version of the abstract.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because phrases which can be implied were used (“The disclosure provides” and “The disclosure further provides”). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The use of the terms Ionis Pharmaceuticals and Pfizer, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Response to Arguments
Applicant's arguments filed January 7, 2026 have been fully considered but they are not persuasive.
The amendment to the abstract filed on January 7, 2026 does not comply with the requirements of 37 CFR 1.121(b) because all amendments are not shown with markings relative to the immediate prior version of the abstract. Therefore, the abstract has not been entered and the Examiner is maintaining the objection to the abstract.
Contrary to Applicant’s assertions, the specification was not amended to include a proper commercial symbol following the terms Ionis Pharmaceuticals and Pfizer. See for example pages 2 and 5 of the specification filed on January 7, 2026. Therefore, the Examiner is maintaining the objections to the specification in reference to the use of trade names and marks.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 77 is 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.
Claim 77 recites the limitation "the one or more proteins". There is insufficient antecedent basis for this limitation in the claim.
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.
Enablement
Claims 1, 5-7, 13, 14, 18-20, 55, and 74-81 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 treating cardiovascular transthyretin (TTR) amyloidosis in a human subject comprising administering patisiran and treating TTR amyloidosis polyneuropathy in a human subject comprising administering patisiran, does not reasonably provide enablement for treating cardiovascular transthyretin (TTR) amyloidosis in a human subject comprising administering any other nucleic acid therapeutic agent or treating TTR amyloidosis polyneuropathy in a human subject comprising administering any other nucleic acid therapeutic agent. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is
sufficient evidence to support a determination that a disclosure does not satisfy the
enablement requirement and whether any necessary experimentation is "undue".
These factors include, but are not limited to: (A) The breadth of the claims; (B) The
nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary
skill; (E) The level of predictability in the art; (F) The amount of direction provided by the
inventor; (G) The existence of working examples; and (H) The quantity of
experimentation needed to make or use the invention based on the content of the
disclosure. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Breadth of claims and nature of the invention:
Claim 1 is drawn to a method of treating cardiovascular transthyretin (TTR) amyloidosis in a human subject comprising administering to the subject a nucleic acid therapeutic agent that reduces expression of TTR. The broadest reasonable interpretation of claim 1 is that the method encompasses treating cardiovascular transthyretin (TTR) amyloidosis in a human subject comprising administering to the subject any nucleic acid therapeutic agent that reduces expression of TTR.
Claim 55 is drawn to a method of treating TTR amyloidosis polyneuropathy in a human subject comprising administering a nucleic acid therapeutic agent that reduces expression of TTR. The broadest reasonable interpretation of claim 55 is that the method encompasses treating TTR amyloidosis polyneuropathy in a human subject comprising administering any nucleic acid therapeutic agent that reduces expression of TTR.
State of the prior art, level of predictability in the art, and level of one of
ordinary skill:
A review of the prior art shows that the state of the art of treating a subject having cardiovascular transthyretin (TTR) amyloidosis or TTR amyloidosis polyneuropathy comprising determining the level of neurofilament light chain (NfL) is immature and nascent.
Carroll et al. (Journal of Neurology, Neurosurgery & Psychiatry 2022) discloses that plasma neurofilament light chain (NfL) is emerging as a useful prognostic biomarker in ATTR-PN [page 671, right column, last paragraph].
Romano et al. (European Journal of Neurology 2024) discloses that serum NfL seems to be a promising biomarker of peripheral nerve involvement in ATTRv amyloidosis and might become a reliable, objective measure to detect the transition from the presymptomatic stage to the onset of symptomatic disease. However, further longitudinal studies are needed to confirm such a role and determine whether it could equally represent a biomarker of disease progression and response to therapy [abstract].
Amount of direction provided by the inventor and existence of working
examples:
Example 1 discloses plasma proteome analysis of patients with hereditary transthyretin-mediated (hATTR) for biomarkers of disease and treatment response. Plasma levels for 1164 unique proteins were analyzed in 136 patisiran treated patients wherein the patients were diagnosed with hATTR. NfL was the most significantly changed protein in the analysis when comparing placebo and patisiran treated hATTR patients over time. Patients diagnosed with hATTR with polyneuropathy had over 4-fold higher levels of NfL in their plasma relative to healthy controls. A significant decline in NfL levels at 9 months that was sustained at 18 months was observed in the patisiran-treated group; whereas, the levels of NfL in the placebo group increased at 9 months and 18 months relative to baseline. At 18 months, patients treated with patisiran had 2-fold lower NfL levels than placebo treated patients. Thus, treatment with patisiran significantly lowered NfL levels in patients with hATTR toward levels observed in healthy controls. Applicant also demonstrated a correlation between neuropathy impairment score and levels of NfL (e.g., decreasing levels of NfL are associated with an improvement in the neuropathy impairment score).
Example 2 discloses treating a subject diagnosed with cardiovascular TTR amyloidosis, with or without a TTR mutation associated with TTR amyloidosis, with tafamidis. A significant increase in NfL is observed as compared to an earlier sample from the subject. When the NfL level is elevated, treatment with tafamidis is discontinued and treatment with patisiran is initiated. Over time, the NfL level is decreased thus indicating that patisiran is effective in treating TTR amyloid polyneuropathy.
Example 4 evaluated the safety and efficacy of revusiran in patients with transthyretin (TTR) mediated Familial Amyloidotic Cardiomyopathy; however, revusiran treatment was stopped after a median of 6.71 months due to an observed mortality imbalance between treatment arms. Therefore, no NfL level was assessed at the close of the study. The V122I mutation in TTR is typically associated with cardiac manifestations rather than neuropathy manifestations of hATTR amyloidosis. Patients with V122I mutations were found to have elevated plasma NfL compared to healthy controls. Therefore, the data demonstrates the utility of NfL level to monitor progression of TTR amyloidosis prior to the development of significant neurological symptoms of the disease or in patients with mutations typically associated with cardiac manifestations of TTR amyloidosis.
The instant specification as filed envisions that the therapeutic agent that reduces the expression of TTR is a nucleic acid therapeutic wherein the nucleic acid therapeutic is an RNAi agent or an antisense oligonucleotide selected from patisiran, vutrisiran, inotersen and ION-TTR-LRx [page 8, lines 15-18]. However, the specification as filed does not disclose any working examples of therapeutic agents other than patisiran.
Quantity of experimentation:
In view of the breadth of the claims which embrace treating cardiovascular transthyretin (TTR) amyloidosis in a human subject comprising administering to the subject any nucleic acid therapeutic agent that reduces expression of TTR and treating TTR amyloidosis polyneuropathy in a human subject comprising administering any nucleic acid therapeutic agent that reduces expression of TTR, the state and level of predictability in the art, the lack of working examples to show treatment of cardiovascular transthyretin (TTR) amyloidosis and TTR amyloidosis polyneuropathy in a human subject comprising administering nucleic acid therapeutic agents other than patisiran, and the failure to provide adequate guidance to overcome the state and level of predictability of the art, one of skill would have to perform undue experimentation in order to practice the invention commensurate in scope with the claims.
Response to Arguments
Applicant's arguments filed January 7, 2026 have been fully considered but they are not persuasive.
Applicant asserts that claims 1 and 55 have been amended to limit the therapeutic agent to a specific group of agents (e.g., a nucleic acid therapeutic agent) which have been demonstrated in the working examples and the art to be effective. Applicant further asserts that the specification provides sufficient enablement for methods for treating cardiovascular transthyretin (TTR) amyloidosis or TTR amyloidosis polyneuropathy by administering a nucleic acid therapeutic agent, e.g., patisiran, to a subject identified as having an elevated level of NfL as compared to a reference level.
This argument is not found persuasive. It is noted that an opinion as to the effectiveness of nucleic acid therapeutic agents has been made; however, no evidentiary support has been provided for the opinion. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP 2145(I) and 716.01(c)(II). Nonetheless, although claim 1 part (d) and claim 55 part (d) were amended to recite a nucleic acid therapeutic agent, the claims as currently written still encompasses administering to the subject any nucleic acid therapeutic agent that reduces expression of TTR. As discussed in the rejection above, the specification, while being enabling for treating cardiovascular transthyretin (TTR) amyloidosis in a human subject comprising administering patisiran and treating TTR amyloidosis polyneuropathy in a human subject comprising administering patisiran, does not reasonably provide enablement for treating cardiovascular transthyretin (TTR) amyloidosis in a human subject comprising administering any other nucleic acid therapeutic agent or treating TTR amyloidosis polyneuropathy in a human subject comprising administering any other nucleic acid therapeutic agent. Therefore, the Examiner is maintaining the 35 U.S.C. 112(a) enablement rejection.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached on (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637