DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 17 February 2026 have been entered. Claims 1-2, 6, 9-12, 15-16, 18-19, 21, 23, and 25-26 were previously pending in the application. Claims 9 and 15 have been cancelled, and no new claims have been added by Applicant. Claims 1-2, 6, 10-12, 16, 18-19, 21, 23, and 25-26 are currently pending in the application. Claims 1, 11, and 18 are independent claims.
The following election of species remains in effect in the instant application:
1)a.iii. targeting moiety: neurotrophic viral vector specific for the central nervous system: AAV9; and
2)a. multiple sclerosis.
Claim 26 remains withdrawn from consideration as being directed to a nonelected species, there being no allowable generic or linking claim.
Claims 1-2, 6, 10-12, 16, 18-19, 21, 23, and 25 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a CON of International Application No. PCT/GB2020/052148, filed 07 September 2020, which claims priority to United Kingdom 1912863.6, filed 06 September 2019. Filing of a certified copy of the United Kingdom 1912863.6, filed 06 September 2019, is acknowledged.
Thus, the earliest possible priority for the instant application is 06 September 2019.
37 CFR 1.121(c)
The claim amendments filed 17 February 2026 is objected to under 37 CFR 1.121(c) because Applicant’s claim listing is not in compliance with 37 CFR 1.121(c) which states that the claim listing must provide the status of all claims, that all claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of "currently amended," and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived.
Specifically, amended claim 10 is marked “Currently amended” and comprises some markings indicating insertions and deletions from the previous version. However, amended claim 10 includes new the text “, such as the blood-brain barrier” in line 3 which is not marked with an underline to indicate the addition of new text to the claim.
Additionally, amended claim 11 is marked “Currently amended” and comprises some markings indicating insertions and deletions from the previous version. However, amended claim 11 has the previously presented word “organ” in line 5 presented with both a strike-through and an underline.
Amended claim 12 is marked “Currently amended” and comprises some markings indicating insertions and deletions from the previous version. However, amended claim 12 omits the deleted text “or” from line 5 of the prior version of the claim (i.e., between “AAVrh10,” and “AAV9” in lines 2-3 of the current version of the claims filed 17 February 2026) which should be present and marked with a strikethrough.
Amended claim 16 is marked “Currently amended” and comprises some markings indicating deletions from the previous version. However, amended claim 16 includes new the text “, such as the blood-brain barrier” in lines 3-4 which is not marked with an underline to indicate the addition of new text to the claim.
In the interests of compact prosecution, the claim listing has been entered. However, future claim listings must include the correct status of all claims, along with the appropriate mark-ups for changes to the claims, in order for the claim listing to meet the requirements for entry under 37 CFR 1.121(c) or a Notice of Non-Compliant Amendment will be mailed to applicant.
Claim Objections
The objection to amended claim 11 for not underlining the inserted text “encoding” is withdrawn. Note, however, that previously amended text should not be underlined in subsequent claim listings. See 37 CFR 1.121(c), which states that the claim listing must provide the status of all claims, that all claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of "currently amended," and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims, and that the text of all pending claims not being currently amended shall be presented in the claim listing in clean version, i.e., without any markings in the presentation of text. The presentation of a clean version of any claim having the status of "original," "withdrawn" or "previously presented" will constitute an assertion that it has not been changed relative to the immediate prior version, except to omit markings that may have been present in the immediate prior version of the claims of the status of "withdrawn" or "previously presented."
The objection to amended claim 18 for reciting “claim11” is withdrawn in view of the amendment to claim 18 to recite “claim 11”.
Claim Rejections - 35 USC § 112(b)
The rejection of amended, previously presented, and cancelled claims 6, 9, 11-12, 15-16, 18-19, 21, 23, and 25 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for multiple issues of indefiniteness is withdrawn over cancelled claims 9 and 15 and maintained over claims 6, 11-12, 16, 18-19, 21, 23, and 25. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Regarding amended claims 6 and 12, Applicant’s amendments to the claims have addressed the issues related to recitation of “variants and derivatives thereof”. However, recitation of “an adeno-associated virus selected from AAVrh.8, AAVrh10, AAV9 or PHP.B” is still indefinite because it is unclear whether the list of AAV viruses is a closed list or an open list. As such, the metes and bounds of the claims still cannot be determined.
Regarding amended claim 11, Applicant amended to claim to recite “wherein IL-2 is expressed specifically in the central nervous system from an exogenous IL-2 encoding sequence” in lines 5-6, which is still indefinite because it is still unclear how IL-2 is expressed specifically in the central nervous system as a part of a pharmaceutical composition comprising a gene encoding IL-2 and a targeting moiety. For example, it is unclear whether the pharmaceutical composition further comprises the central nervous system, such that the IL-2 is being specifically expressed by the central nervous system within the pharmaceutical composition, or whether the IL-2 gene is merely structured for specific expression in the central nervous system, such that upon administration to the central nervous system would result in specific expression within the central nervous system. As such, the metes and bounds of the claim still cannot be determined. Amended and previously presented claims 12, 16, 18-19, 21, 23, and 25 are included in this rejection due to their dependence on, or encompassing of, independent claim 11.
Regarding claim 23, Applicant’s amendment to make claim 23 dependent from claim 21 has addressed the issue of antecedent basis for “the inflammation of the brain”.
Regarding the issues underlying the maintenance of this rejection, Applicant argues that:
the amendment to claims 6 and 12 to remove “variants and derivatives thereof” has overcome the rejection of amended claims 6 and 12; and
amended claim 11 has been amended to clarify that IL-2 is expressed specifically in the CNS from an exogenous IL-2 encoding sequence driven by the CNS-specific promoter, and as such it is not clear how IL-2 is specifically expressed in the CNS.
However, this is not agreed.
Regarding Applicant’s argument 1), as described above, the amendments addressed one issue of indefiniteness recited in the prior versions of claims 6 and 12, but did not address the issue related to whether the options for the AAV is an option or a closed group.
Regarding Applicant’s argument 2), Applicant’s amendments have improved the clarity of the claim by specifying that the expression is CNS expression. However, the amendments have not addressed the issue of indefiniteness in that “is expressed” is an active process which is inconsistent with a product claim. As such, it is unclear whether Applicant is intending to claim the CNS tissue in the composition itself such that the expression is occurring within the claimed composition or whether Applicant merely means to recite an intended use for the composition such that the gene encoding IL-2 is configured for expression in the CNS.
As such, the metes and bounds of the claims still cannot be determined, and the rejection is maintained.
**The following new rejection is necessitated by Applicant’s amendments to the claims.
Amended claims 10-12, 16, 18-19, 21, 23, and 25 are newly 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.
Regarding amended claims 10 and 16, the newly recited phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). As such, the metes and bounds of the claim cannot be determined.
Regarding amended independent claim 11, claim 11 newly recites, “an exogenous IL-2 encoding sequence” in line 6, which is indefinite because it is unclear whether the exogenous IL-2 encoding sequence recited in line 6 is meant to be the same as the “a gene encoding interleukin-2 (IL-2)” recited in lines 1-2. As such, the metes and bounds of the claim cannot be determined.
Amended and previously presented claims 12, 16, 18-19, 21, 23, and 25 are included in this rejection due to their dependence on, or encompassing of, independent claim 11.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, and cancelled claims 1-2, 6, 9-12, 15-16, 18-19, 21, 23, and 25 under 35 U.S.C. 103 as being unpatentable over Deverman & Gradinaru (US20170166926A1), published 15 June 2017, in view of Hao et al. 2011, Ann. Neurol., 69(4), 721-734; Xu et al. 2019, International Immunopharmacology, 72, 322-329, published online 18 April 2019; Frischer et al. 2009, Brain, 132, 1175-1189; and Baker & Hankey 2003, Gene Therapy, 10, 844-853, is withdrawn over cancelled claims 9 and 15 and maintained over amended and previously presented claims 1-2, 6, 10-12, 16, 18-19, 21, 23, and 25. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant has amended independent claim 1 to recite “wherein administration of IL-2 comprises tissue- or organ-specific expression of IL-2 in the central nervous system of said subject from an exogenous IL-2 encoding sequence driven by a central nervous system-specific promoter” in lines 6-8. Applicant additionally amended independent claim 11 to recite, “wherein IL-2 is expressed specifically in the central nervous system from an exogenous IL-2 encoding sequence driven by a central nervous system-specific promoter” in lines 5-6.
However, as discussed in the prior actions, Deverman was cited for teaching IL-2 as one of a finite list of identified proteins to target for expression in the CNS using a neurotrophic AAV9 vector [0183]. Additionally, Hao and Xu were further relied on for teaching the specific connection between IL-2 and both MS and Treg cell expansion, providing the specific motivation to select IL-2 from the list provided in Deverman for both the methods and compositions taught by Deverman.
`Deverman was also cited for teaching that the therapeutic protein expression is driven by a central nervous system-specific promoter [0148, 0198-200]. Deverman also teaches the specific use of the GFAP promoter which specifically drives expression in astrocytes, the Vgat promoter which specifically drives expression in GABAergic neurons, and the Vglut2 promoter which specifically drives expression in glutaminergic neurons [0240, 0260, 0266, 0273-0274].
As such, Applicant’s amendments do not overcome a finding of obviousness under 35 U.S.C. 103 over Deverman, Hao, Xu, Frischer, and Baker.
Applicant argues that:
the amendment of independent claims 1 and 11 to recite/clarify that the IL-2 is expressed specifically in the CNS from an exogenous IL-2 encoding gene driven by a CNS-specific promoter makes it clear that administration and/or IL-2 expression is limited to the CNS, a systemic/peripheral IL-2 administration/expression is excluded from the claim scope; and
the maintenance of previously submitted arguments that the cited references teach non-targeted systemic IL-2 expression, and would thus not be considered by the person of ordinary skill in the art in seeking to limit IL-2 expression to the CNS due to the well-known untenable side effects of systemic IL-2 expression.
However, this is not agreed.
Regarding Applicant’s argument 1), as discussed above, Deverman was cited for teaching IL-2 as one of a finite list of identified proteins to target for expression in the CNS using a neurotrophic AAV9 vector [0183]. Additionally, Hao and Xu were further relied on for teaching the specific connection between IL-2 and both MS and Treg cell expansion, providing the specific motivation to select IL-2 from the list provided in Deverman for both the methods and compositions taught by Deverman.
Regarding Applicant’s argument 2), although Deverman teaches systemic administration, Deverman teaches specific transduction and expression of the therapeutic protein in the CNS, such that Deverman was cited for teaching that the neurotrophic AAV9 viral vector, specifically a variant PHP.B AAV, such as the AAV-PHP.B2, AAV-PHP.B3, or AAV-PP.N variants have increased CNS transduction compared to AAV9 and/or the parent AAV-PHP.B vector [0048-0049, 0053, 0056, Table 5].
Deverman was also cited for teaching that the AAV-PHP.B, AAV-PHP.B2, and AAV-PHP.B3 vectors cross the blood-brain barrier which separates the brain tissue/organ from other tissues or organs of the subject by teaching systemic administration of the viral vector encoding Neon Green followed by assessment of brain sections showing expression of Neon Green within the brain tissues [0056, 0260, Figure 9]. Deverman was also cited for teaching that the therapeutic protein expression is driven by a central nervous system-specific promoter [0148, 0198-200]. Deverman also teaches the specific use of the GFAP promoter which specifically drives expression in astrocytes, the Vgat promoter which specifically drives expression in GABAergic neurons, and the Vglut2 promoter which specifically drives expression in glutaminergic neurons [0240, 0260, 0266, 0273-0274].
Deverman was additionally cited for teaching a method of treating multiple sclerosis (MS) comprising administering to a subject in need thereof (e.g., a subject identified as having multiple sclerosis) a therapeutically effective amount of an AAV vector that includes a polynucleotide that encodes a tropic or immunomodulatory factor, wherein the AAV vector includes a capsid protein that includes a targeting peptide (e.g., AAV-PHP.B, AAV-PHP.B2, AAV-PHP.B3, or AAV-PHP.N) which allows proper targeting of the said factor to be expressed in the nervous system [0298, SEQ ID NOs: 1-4].
Therefore, Deverman teaches the specific expression of the therapeutic protein, including IL-2, in the CNS driven by a CNS-specific promoter.
Additionally, Xu was cited for teaching that even though IL-2’s diverse functions, short half-life, toxicity, and off-target effects have limited its use for autoimmune disorders [abstract, column 2 ¶ 1-column 3 ¶ 1], other approaches like IL-2/mAb complexes, IL-2 muteins, and low dose IL-2 emerged and revived IL-2 therapeutic strategies for autoimmune diseases [column 3 ¶ 1]. Xu also teaches that administration of low dose IL-2 has got a wide range of applications in several clinical settings to restore Treg cell populations and treat autoimmune diseases by expanding Treg cells and balancing the Treg/Teff ratio, which is important for the immune homeostasis [column 11 ¶ 1, column 12 ¶ 1-2]. Xu also teaches that the various IL-2 therapeutics selectively target on Treg cells to induce immunosuppression and maintain immune tolerance with relatively mild efficacy and low toxicities [column 12 ¶ 2]. Therefore, given the teachings of Xu, an ordinarily skilled artisan would not have been dissuaded from considering the cited references to arrive at the claimed invention due to “well-known untenable side effects of systemic IL-2 expression”.
As such, Applicant’s amendments and arguments do not overcome a finding of obviousness under 35 U.S.C. 103 over Deverman, Hao, Xu, Frischer, and Baker, and the rejection is maintained.
Conclusion
No claim is 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.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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