DETAILED ACTION
The Examiner of your application in the USPTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Examiner Bryan William Heck in Art Unit 1643.
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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/22/2026 has been entered.
Claims Status
Claims 22-30 are pending. Claims 23-24 are withdrawn as directed to a non-elected species. Claims 22 and 25-30 are examined on the merits.
Priority
As outlined in the previous office actions, priority for the instant application is set to 06/06/2018 of PCT/US2018/036261, which provides the earliest support for the claimed subject matter.
Rejections Withdrawn
The rejection under 35 USC 103 in the Final Rejection mailed 10/23/2025 (Pages 5-8) is withdrawn in view of applicant’s arguments and in view of new references supplied.
New Rejections
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.
Claims 22 and 25-30 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.
Claim 22 recites the limitation “wherein administering the therapeutically effective amount of the anti-CD3 antibody reduces microglial activation by about 20%”. However, it is unclear to what the 20% reduction is compared (i.e. reduces microglial activation by 20% relative to what?). Moreover, it is unclear how the percent activation is calculated or determined (i.e. what specifically is encompassed by “activation” and what values are measured to determine this?), or if this 20% change in “activation” is regarding the proportion of “activated” microglial cells (i.e. 20% fewer activated cells) or the level of “activation” of the cells (i.e. any given cell being 20% less “activated”, as determined by a prescribed set of molecular markers).
Claims 25-30 depend from Claim 22 and are rejected for the same reasons.
Because the scope of the claims could not be determined, the claims have been examined relative to “microglial activation” in the generic under its broadest reasonable interpretation.
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 22 and 25-30 are rejected under 35 U.S.C. 103 as being unpatentable over Mayo et al. 2016 (Brain, 139(7), 1939-1957.; of record), herein “Mayo”, and in view of Chio et al. 2015 (Current medicinal chemistry 22.6 (2015): 759-770.; PTO-892), herein “Chio”, Li et al. 2015 (Chinese medical journal, 128(08), 1072-1078.), herein “Li”, Brody et al. 2015 (Molecular and Cellular Neuroscience, 66, 91-98.; of record), herein “Brody”, and Kuhn and Weiner 2016 (Immunotherapy, 8(8), 889-906.), herein “Kuhn”, and as evidenced by the instant specification.
Mayo teaches a method for treating central nervous system (CNS) inflammation comprising nasal administration of an anti-CD3 antibody (Abstract; Fig. 1).
Mayo teaches that the anti-CD3 treatment resulted in increased number of regulatory T cells (Tregs) and a corresponding increase in IL-10 expression (Fig. 2-3).
Mayo teaches that the therapeutic effect of the nasal anti-CD3 antibody was abrogated when IL-10 is blocked (Pg. 1945 Col 1; Fig. 2L).
Mayo teaches that nasal anti-CD3 treatment resulted in upregulation and downregulation of a variety of genes associated with microglial activation, which shifted the “microglial phenotype towards an anti-inflammatory pattern” (Fig. 7; Pg. 1952, Col. 1).
Mayo teaches that this change in microglial phenotype was dependent on IL-10, and that knockdown of microglial Il10ra reversed the therapeutic benefit of nasal anti-CD3 antibody (Fig. 7; Pg. 1952, Col. 2).
Mayo speculates that this therapeutic approach may be helpful in treating other types of central nervous system inflammation (Abstract).
Mayo does not teach that the anti-CD3 antibody comprises the instantly claimed sequences nor that the method taught therein could be used to treat traumatic brain injury, such as repetitive concussive injury. These deficiencies are cured by Chio, Li, Brody, and Kuhn.
Chio teaches that microglia and inflammatory cytokines are involved in traumatic brain injury (TBI) (Abstract). Chio teaches that during the acute phase of TBI, increases in proinflammatory cytokines and decreases in anti-inflammatory cytokines such as IL-10 leads to activation of the “M1” subtype of microglia, which causes tissue damage and loss of neurons (Pg. 765, last ¶). Chio proposes microglia activation as a “compelling target” in the treatment of TBI (Title) and suggests that attenuating the activation of microglia could improve outcomes in patients with TBI (Pg. 766, last ¶).
Li teaches that Treg cells downregulate inflammatory factors and are neuroprotective in the context of traumatic brain injury (TBI) (§ Discussion; Pg. 1075, last ¶). Li teaches that increased percentages of circulating Tregs in patients with traumatic brain injury were associated with better outcomes, whereas patients having poor outcomes had significantly fewer Tregs (Abstract; § Discussion; Pg. 1077, ¶3). Li suggests that Tregs could be used as a therapeutic target in the treatment of TBI and that increasing Tregs in a patient may improve outcomes after TBI (§ Discussion; Pg. 1077).
Brody teaches that microglial activation is a “prominent and consistent features in many animal [repetitive concussive traumatic brain injury] models” and has been reported following human TBI, including concussive injury (Pg. 94, § “4. Microglial activation”).
Kuhn teaches that Foralumab (aka 28F11-AE; NI-0401) “is so far the only entirely human anti-CD3 mAb, and that “[t]he completely human origin further decreases side effects that have been previously noted with other humanized anit-CD3 mAb” (Pg. 895). Kuhn further teaches that anti-CD3 mAbs can be administered nasally, which “seems to be a very safe and promising therapeutic approach” (Pg. 894, Col. 2).
As evidenced by the instant specification, Foralumab comprises the instantly claimed CDR, VH/VL, HC/LC sequences as specified in Claim 22 and 27-28: “This anti-CD3 antibody is referred to herein as NI-0401, Foralumab, or 28F11-AE” (Pg. 12).
First, it would have been obvious to one of ordinary skill in the art that the method of treatment comprising nasal administration of an anti-CD3 antibody according to the teachings of Mayo could be used to treat traumatic brain injury (TBI) including repetitive concussive injury.
The skilled artisan would have been motivated by the suggestion of Chio that microglial activation could be targeted to treat TBI, the suggestion by Li that Tregs are a promising therapeutic target in TBI, and the suggestion by Mayo that nasal anti-CD3 may be helpful in treating additional types of CNS inflammation.
There would have been a reasonable expectation of success because Brody teaches that microglial activation is a “prominent and consistent feature” of repetitive concussive TBI, Chio and Li teach that reduced microglial activation and increased Treg counts are associated with better TBI outcomes, respectively, and Mayo teaches that nasal anti-CD3 reduces CNS inflammation by upregulation of Tregs, increased IL-10, and reduced microglial activation.
Additionally, it would have been obvious to one of ordinary skill in the art to substitute the anti-CD3 antibody of Mayo with Foralumab as taught by Kuhn. The skilled artisan would have been motivated to make this substitution, for example, in order to adapt the method of Mayo, which was performed in a mouse model, for the treatment of humans by employing a fully human antibody, and because, at the time, Foralumab was “the only entirely human anti-CD3 mAB”. There would have been a reasonable expectation of success because Mayo teaches that the human origin of Foralumab decreases side effects and suggests that nasal administration of anti-CD3 mAbs is a safe and promising therapeutic approach.
Response to Arguments
Applicant's arguments filed 01/22/2026 have been fully considered but they are not persuasive.
Briefly, as the arguments relate to the new rejection set forth above, although Applicant agrees that the primary reference Mayo “describes a decrease in microglial activation after treatment with anti-CD3 antibody”, Applicant asserts that the skilled artisan would not have found obvious to use the treatment method of Mayo to treat traumatic brain injury (TBI) because method of Mayo is performed in the context of a different CNS inflammatory condition, multiple sclerosis (Remarks, Pg. 5, ¶3). Applicant further asserts that Brody fails to cure this deficiency because Brody is “silent regarding reducing microglia activation for treating TBI” (Remarks Pg. 6, ¶2).
In response, applicant is directed to newly incorporated references Chio et al. 2015 (Current medicinal chemistry 22.6 (2015): 759-770.; PTO-892) and Li et al. 2015 (Chinese medical journal, 128(08), 1072-1078.) (summarized in detail above), which relate to inflammation-related damage following traumatic brain injury (TBI), its mechanistic ties to microglia, and explicit suggestions in that Tregs and microglial activation could be targeted to treat TBI.
Conclusion
No claim is allowed.
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/BRYAN WILLIAM HECK/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643