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 .
Status of the Application
The claims of 18 December 2024 are entered.
The election of 23 July 2026 is entered.
Claims 1-15 are pending. Claims 2-6, 8, and 10-15 are withdrawn with traverse. Claims 1, 7, and 9 are being examined on the merits.
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-9), a conjugate of fluocinolone acetonide and rhNGF, and inflammation caused by or associated with Alzheimer’s disease in the reply filed on 23 July 2026 is acknowledged. The traversal is on the ground(s) that there is no burden to search both inventions. This is not found persuasive because search burden is not a consideration for restriction of inventions under 35 U.S.C. 371.
The requirement is still deemed proper and is therefore made FINAL.
Claims 2-6, 8, 10-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 23 July 2026.
Claim Objections
Claim 7 is objected to because of the following informalities: a period occurs within the body of the claim (see e.g. line 5). A period may only appear at the end of a claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-9 are rejected 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 requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims utilize a conjugate comprising an active agent compound covalently bonded to a protein, peptide, or peptidomimetic that binds selectively to a neurotrophin receptor. This is a very broad genus as discussed below.
The active agent compound is broad and has no real limit on structure. In the specification, embodiments that offer more narrow options are provided but in no instance is a definition of an active agent compound provided that might offer insight as to what limits are present on that element of the conjugate (see e.g. p.5-6, 18). Given this lack of definition, the broadest reasonable interpretation of the claimed active agent is that it is any compound that has bioactivity. Accordingly, there is no reasonable calculation of the number of species within this subgenus.
A few more specific compounds are disclosed in the specification, including a glucocorticoid, including fluocinolone acetonide, but also can be an antimicrobial or antiviral compound, an anti-cancer compound, an agent to block receptor binding of neuropilin-1, or an antibody.
The protein, peptide, or peptidomimetic that binds selectively to a neurotrophin receptor is defined by function rather than by a particular structure beyond having a backbone characterized by peptide bonds, or in the case of a peptidomimetic a modified backbone.
The specification discloses several proteins as meeting this requirement including NGF, BDNF, NT-3, NT-4/5, NT-6, NT-7, GDNF, CNTF, derivatives, analogs, and fragments thereof, and synthetic peptides binding to nerve cell receptors and having agonist or antagonist activity. This is a more restricted genus if considering these features, but the claim as written encompasses any protein, peptide, or peptidomimetic that selectively binds to a neurotrophin receptor. Again, the genus is broad given the broadest reasonable interpretation.
The claim also requires that the conjugate serve to treat neuroinflammation. No reasonable correlation is established in the specification that a genus of any active agent compound conjugated to a protein, peptide, or peptidomimetic that selectively binds to a neurotrophin receptor serves to treat neuroinflammation. The claims also require a variety of neuroinflammatory conditions including viral encephalitis, inflammation of the optic nerve, acute disseminated encephalomyelitis, COVID-19 associated acute disseminated encephalomyelitis, and inflammation of vitreous retinal ganglion cells. No correlation is established in the specification between the genus of conjugates and the ability to treat any of the neuroinflammatory conditions, nor is there any experimental data showing that any species of the genus can treat these conditions.
The claimed genus is broad. A single compound is disclosed as FA-rhNGF. The rhNGF is reasonably interpreted as recombinant human nerve growth factor. The FA is not defined anywhere in the specification. Based upon Applicants’ species election this appears to be fluocinolone acetonide, but there is no reasonable conclusion from the specification as filed that this is the case. For instance, FA could also represent folic acid, formic acid, or ferulic acid. Even assuming that the compound is a conjugate between fluocinolone acetonide and rhNGF, this would be a single species from an incalculable genus. There is no reasonable assurance that any member of the genus serves to treat neuroinflammation.
Essentially, the claims are directed to an extremely broad genus with at best a single species disclosed, and no reasonable structure-function correlation established to lead to a nexus between the genus and treatment of neuroinflammation. The skilled artisan would not recognize possession of the genus as claimed. Accordingly, written description is lacking.
Dependent claim 8 also recites an antibody target but does not indicate any particular structure for the antibody. Per MPEP 2163 II. A. 3. (a) disclosure of an antibody that is defined by its antigen is insufficient to provide adequate written description. Antibodies are generally discussed in the specification, but the only specifically disclosed antibodies are bamlanivimab, casirivimab, imdevimab, and etesevimab. Each of these target the COVID-19 spike protein and are not configured to block receptor binding to NRP1 as claimed. The skilled artisan would not recognize possession of any antibodies configured to block receptor binding of NRP1.
The “small molecule compound configured to block receptor binding of NRP1” similarly is claimed and discussed in the specification by what it binds rather than by structure. There is no apparent disclosure of any actual small molecules nor guidance on the structure required to achieve a compound that blocks receptor binding of NRP1. The onus is placed on the skilled artisan, who would not recognize possession of any small molecules that block receptor binding of NRP1.
Considered as a whole, the claims lack written description.
Claims 1-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
“[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech Inc. v. Novo Nordisk 108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997); In re Wright 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); See also Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir. 1991); In re Fisher 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Further, in In re Wands 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) the court stated:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman [230 USPQ 546, 547 (BdPatAppInt 1986)]. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredict-ability of the art, and (8) the breadth of the claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Nature of the Invention
The invention is drawn to a method of treating neuroinflammation by administering one or more active agent compounds covalently bonded to a protein, peptide, or peptidomimetic that binds to a neurotrophin receptor.
Breadth of the Claims
The claims are broadly written. Neuroinflammation covers inflammation in any part of the nervous system. The active compound is claimed only by activity and not via any particular structure. The protein, peptide, or peptidomimetic to which the active agent is conjugated is claimed by its target rather than by any particular structure.
State of the Prior Art
A conjugate between fluocinolone acetonide and rhNGF was shown to be effective in a rat model of zoster-induced pain (see e.g. Webb et al. J. Pain 9:A1-A14, published April 2008). The same conjugate is present and discussed as useful for nerve delivery, and corticosteroids such as fluocinolone acetonide are discussed as being useful for inflammation (see e.g. US 6,887,861 B1).
While fluocinolone acetonide was known for use as corticosteroid in topical anti-inflammatory applications there is no evidence it was considered as useful in treatment of neuroinflammation alone or with another protein or peptide (see e.g. https://medlineplus.gov/druginfo/meds/a682271.html). Petralia et al. (Brain Sci. 12:827, published June 2022) suggest that rather than treating Alzheimer’s disease, fluocinolone acetonide might be a drug the predisposes a subject towards Alzheimer’s disease (see e.g. Table 3).
Minnone et al. (Int J Mol Sci 18:1028, published May 2017) describe NGF as having both anti- and pro-inflammatory actions, since it both activates immune responses to promote inflammation while also activating pathways to dampen response in tissues and limit overall damage.
Relative Skill of those in the Art
The relative skill of those in the art is high.
Predictability or Unpredictability of the Art
There is a general lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970).
Amount of Direction or Guidance Given
The specification discusses use of neurotrophin receptor binding compounds conjugated to an active agent to neuroinflammation, including that caused by brain cancer, MS, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, prion disease, ALS, frontotemporal dementia, chronic pain, and viral infection. The protein, peptide, or peptidomimetic is discussed as being overlapping with that found in claim 7. The active agent is described as being a glucocorticoid, including fluocinolone acetonide, but also can be an antimicrobial or antiviral compound, an anti-cancer compound, an agent to block receptor binding of neuropilin-1, or an antibody.
Presence/Absence of Working Examples
The working examples discusses only the compound FA-rhNGF. This presumably is the elected fluocinolone acetonide conjugated to recombinant human nerve growth factor, but notably the specification never indicates that FA stands for fluocinolone acetonide. There is no reasonable disclosure in the prior art that the skilled artisan necessarily recognizes the abbreviation FA as standing for fluocinolone acetonide.
The working examples using the FA-rhNGF only concern a rat model of inflammatory pain. The results would appear to indicate that FA-rhNGF can ameloriate neuroinflammation due to pain. However, this is not reasonably extended to (1) the elected compound or (2) to neuroinflammation caused by or associated with Alzheimer’s disease. This also does not extend more broadly to the genus of compounds and neuroinflammation in general. In the case of (1), as noted above the skilled artisan has no reasonable assurance that FA-rhNGF means that the compound is (fluocinolone acetonide)-rhNGF since the active agent is never defined as being represented by FA in the specification. In the case of (2), there is no reasonable correlation established that a model of neuroinflammation due to pain extends to treating inflammation caused by or associated with Alzheimer’s disease since the etiology and pathology of the conditions are disparate. There is no reasonable correlation established that the nerve pain model extends to all forms of neuroinflammation.
Quantity of Experimentation Necessary
The specification and claims lead to a conjugate where the active agent is broadly defined and the protein, peptide, or peptidomimetic is defined only by a target rather than by any structure. While full-length proteins are discussed, no smaller peptides are discussed. Only rhNGF is utilized, and while the model relates to neuroinflammation generally it does not demonstrate treatment of neuroinflammation caused by or associated with Alzheimer’s disease as elected. No models establish treatment of neuroinflammation from viral encephalitis, inflammation of the optic nerve, acute disseminated encephalomyelitis, COVID-19 associated acute disseminated encephalomyelitis, or inflammation of vitreous retinal ganglion cells. No peptidomimetics are discussed. Other than offering the target of neurotrophin receptor binding, the onus is left on the skilled artisan to prepare the compounds for binding with only the most generic disclosure of potential proteins. The active agent as claimed is so broad that any active agent can be added to the protein, peptide, or peptidomimetic binding selectively to a neurotrophin receptor.
Even only considering the conjugate, the level of experimentation required of the skilled artisan is undue. As noted above, the active agent is so broadly claimed that there is no real limit to what form it takes. The protein, peptide, or peptidomimetic is defined by target rather than by any particular structure, leading the work on identifying such members of the genus on the part of the skilled artisan. Just the level of experimentation to make the conjugate is undue.
Compounding the issue is that the skilled artisan must not only make the conjugate as claimed but also use it to treat neuroinflammation. The model as provided treats pain. The compound FA-rhNGF as utilized is not readily ascertainable, but even if it is a conjugate of fluocinlone acetonide and rhNGF, that only represents a single species from a very broadly claimed genus. The model does not demonstrate treatment of neuroinflammation caused by or associated with Alzheimer’s disease, nor any of the other claimed neuroinflammation types. Having to not only make a sufficient number of species covering the breadth of the genus as claimed but also determine if the genus can be used to treat neuroinflammation requires an undue level of experimentation.
In view of the Wands factors as discussed above, it is the Examiner’s opinion that the claims are not fully enabled and one of skill in the art would have to engage in undue experimentation to practice the invention as claimed herein, without a reasonable assurance of success.
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 7 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.
At issue is that claim 1 recites that the conjugate has “a protein, peptide, or peptidomimetic”. Claim 7 recites a first Markush group of options for this protein, peptide, or peptidomimetic including NGF, BDNF, NT-3, NT-4/5, NT-6, NT-7, GDNF, CNTF, and derivatives or fragments thereof, but also recites that the protein, peptide, or peptidomimetic is a β-subunit of NGF, rhNGF, or rhBDNF. It is not clear based upon claim 1 how the protein, peptide, or peptidomimetic can be two options with the “and” conjunction between the first Markush group and the second list of options.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY J MIKNIS whose telephone number is (571)272-7008. The examiner can normally be reached Mon-Thurs 7-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at (571) 270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY J MIKNIS/Patent Examiner, Art Unit 1658
