DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
Specific deficiencies and the required response to this Office Action are as follows:
The incorporation by reference statement states the size of the sequence files in kilobytes rather than the required bytes. Appropriate correction is required.
Status of the Claims
Amendments to the Claims, Declaration Under 37 CFR § 1.130(a), and Arguments/Remarks filed 25 March 2026, in response to the Office Correspondence dated 28 November 2025, are acknowledged.
The listing of Claims filed 25 March 2026, have been examined. Claims 1, 5-7, and 9-12 are pending. Claims 1, 5-7, 9 and 12 are amended and are supported by the originally-filed disclosure. Claims 2-4, 8, and 13-16 are canceled and no new claims have been added.
Response to Amendment
The applicant's arguments have been fully considered and are addressed below in the Response to Arguments. The rejection of canceled claims is moot. New and continued rejections are set forth below.
The rejection of claims 9, and 12 as indefinite under 35 U.S.C. § 112(b) is maintained. New ground of objection and rejection under 35 U.S.C. § 112(b), necessitated by amendment, are set forth below for claims 1, 5-7, and 9-12.
Based on the amended to claim 1, the rejection of claim 1 under 35 U.S.C. § 101 as directed to a judicial exception without significantly more is withdrawn and a new rejection under 35 U.S.C. § 101 is made for claim 1, as amended. The amended to claim 5 necessitates that it is also included in the rejection under 35 U.S.C. § 101.
The rejection of claim 1 under 35 U.S.C. 102(a)(1) as being anticipated by Kieffer-Kwon, is withdrawn, as necessitated by the amendment adding the TREM2 silencer limitation to the claim. The Declaration under 37 CFR § 1.130(a) asserting that the journal article by Li et al., TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway, published in J Neuroinflammation, Volume 18, 257 on 14 October 2022 (hereinafter "Li"), is excepted as prior art under 35 U.S.C. § 102(b)(1)(A) is accepted. Accordingly, the rejections under 35 U.S.C. § 103 are withdrawn. New rejections of the claims 1, 5-7, and 9-12 under 35 U.S.C. § 103 are made as outlined below, absent the use of Li as prior art, as set forth below.
Maintained Rejections
The following rejections are maintained from the previous Office Correspondence dated 28 November 2025, since the art which was previously cited continues to read on the amended/newly cited limitations.
Claim Rejections - 35 USC § 112(b)
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 Applicant regards as his invention.
Claims 9 and 12 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, regards as the invention.
Claim 9 is rejected as indefinite because the open list of possible delivery forms in the claim (e.g., injection, eye drop, eye ointment, hydrogel, ultrasonic ocular drug delivery, drug-loaded contact lenses, drug-eluting implant, nanoparticle-mediated delivery, intravitreal gene therapy, and intravitreal microneedle). Despite amendment to “and/or,” the claim still recites a broad, open-ended list of mutually incompatible delivery modalities. This results in operational inconsistency, as a single composition cannot reasonably embody all listed forms simultaneously. Thus, the claim remains ambiguous in scope and breadth.
Using the conjunction “and” still implies that all of the listed forms are required to be present together, covering only the combination of all the forms used together. The specification definition provided in ¶[0064] does not surmount this rejection, as it only covers singular and plural nouns. This issue does not apply to the limitation using the disjunctive "or", which indicates at least one and any one of the forms is sufficient as an administration form, and the administration forms may be used in the alternative. To overcome this rejection, the applicant is advised to amend the claim to eliminate the use of “and/”.
Claim 12, as amended, now recites “wherein the subject's photoreceptor degeneration is reversed” and the claim remains indefinite. Claim 12 depends from claim 11 and recites, “wherein the subject’s photoreceptor degeneration is reversed.” The antecedent basis for “photoreceptor degeneration” is not properly introduced in any claim from which it depends. Claim 11 recites “rescuing visual function” but does not mention photoreceptor degeneration. Claim 1 from which claim 11 ultimately depends recites “treating a retinal degeneration”, not specifically “photoreceptor degeneration.” Retinal degeneration includes many pathologies (e.g., microglial activation, neuroinflammation, RPE dysfunction) not limited to photoreceptors. The term “photoreceptor degeneration” is thus a new, narrower term lacking antecedent basis, rendering the scope of claim 12 ambiguous (see MPEP § 2173.05(e)). A person of ordinary skill in the art would be left to guess whether "photoreceptor degeneration" refers to the same condition as "retinal degeneration" of claim 1, a subset thereof, or a different condition entirely.
The applicant’s amendment to claim 12 does not cure this defect and cancellation of other claims does not establish antecedent basis for “photoreceptor degeneration” in the remaining chain. To overcome, the applicant must amend claim 11 or claim 1 to explicitly recite “photoreceptor degeneration” as a condition being treated, or amend claim 12 to refer to “the retinal degeneration of claim 1” if supported by specification showing retinal degeneration encompasses photoreceptor degeneration.
In addition, “reversed” is not quantitatively defined for a subject's photoreceptor degeneration. No baseline or measurable standard is provided. It is unclear whether full restoration, partial improvement, or functional stabilization qualifies. To overcome this rejection, the applicant may amend the claims to clarify what objective metes and bounds are intended by the claim.
New Rejections
The following new rejections are made from the previous Office Correspondence dated 28 November 2025, as the Applicant's amendment necessitated the new grounds of rejection presented below based on the amended/newly cited limitations.
Claim Objections
Claim 9 is objected to because of the following informalities:
Claim 9 recites "the administration form comprises..." but lacks connecting verb phrase to claim 6 from which it depends (missing "wherein"). The claim should be amended to "wherein the administration form comprises...". Claim 9 is also missing a period at end of claim and a period should be added after "intravitreal microneedle form" at the end of the sentence.
Claim Rejections - 35 USC § 112(a)
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, 5-7, and 9-12 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 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.
Enablement has been evaluated under the factors set forth in In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988):
Breadth of the claims: Claim 1 broadly encompasses any TPM1 inhibitor, any TREM2 silencer, any retinal degeneration, and any pharmaceutical formulation. The specification enables at most one specific TPM1-targeting siRNA embodiment (Example 2), but provides no TREM2 silencer. Thus, the claims encompass a vast genus far beyond the disclosed embodiments.
Nature of the invention: The invention relates to combination therapy with two different nucleic acid-based agents (TPM1 inhibitor and TREM2 silencer) for treating retinal degeneration. This field is notoriously unpredictable and includes off-target effects, delivery challenges that requires careful formulation and dosing, and synergy vs. antagonism unpredictable interactions. A person of ordinary skill in the art would not be able to predict, without undue experimentation, whether a given TPM1 inhibitor/TREM2 silencer combination would be effective, let alone how to formulate and dose it.
State of the prior art: Even considering the state of the prior art (e.g., Bhattacharjee teaches miRNA-34a as a TREM2 silencer; Kieffer-Kwon teaches KSHV miRNAs as TPM1 inhibitors), the specification provides no bridge between these separate prior art disclosures and the claimed combination. A person of ordinary skill in the art would be left to guess which TPM1 inhibitor to use (e.g., siRNA, miRNA, small molecule, or antibody) and which TREM2 silencer to use (e.g., miRNA-34a, anti-TREM2 siRNA, or shRNA). The specification provides no guidance on such or the ratio to combine them and how to formulate them together. The prior art may make the combination obvious under § 103, but it does not enable the claimed invention.
Level of one of ordinary skill in the art: A person of ordinary skill in the art would have a Ph.D. in molecular biology or ophthalmology, with experience in RNAi and ocular drug delivery. However, even a highly skilled would require substantial experimentation to practice the claimed invention because the specification provides no starting point, no sequence for a TREM2 silencer, no formulation for the combination, no dosing information. The art of combining two different RNAi agents for ocular delivery is not routine and each combination requires optimization.
Unpredictability of the art: The claimed invention lies in a highly unpredictable field involving retinal degeneration biology, RNA interference, ocular nucleic acid delivery, and microglial signaling. RNAi therapeutics are notoriously unpredictable. The interaction between TPM1 inhibition and TREM2 silencing is particularly unpredictable and nuanced (i.e., disease-stage-dependent). Li (Li et al., 2022b), cited by applicant in the specification, teaches that TPM1 inhibition in TREM2-deficient retinas exacerbates inflammation. Thus, one of ordinary skill would not reasonably predict whether the claimed composition would treat retinal degeneration, or worsen retinal degeneration.
Lack of guidance: The specification provides no guidance regarding identity of any TREM2 silencer, design of any TREM2 silencing sequence, how to formulate TPM1 inhibitor plus TREM2 silencer, dosing ratios, concentration ranges, therapeutic window, disease-stage selection, and administration timing. The specification provides no direction or guidance on how to make or use a TPM1 inhibitor that also silences TREM2 either. The disclosure merely states that a TPM1 inhibitor may include a TREM2 silencer. That statement does not enable practice of the full scope (see MPEP § 2164.05).
No working example of the claimed composition: The specification contains examples of a pharmaceutical composition comprising both a TPM1 inhibitor and a TREM2 silencer or a TPM inhibitor that is a TREM2 silencer. The specification contains zero working examples of the claimed composition.
Example 1 is TPM1 upregulation in rd10 mice, it contains no composition, no TREM2 silencer. Example 2 is a TPM1 knockdown (siTPM1), wherein siTPM1 targets TPM1 only is not a TREM2 silencer. Example 3 is TPM1 overexpression, which is the opposite of inhibition and contains no TREM2 silencer. Example 4 is a TREM2 knockout (genetic) mouse alone which downregulates TPM1, however a genetic knockout mouse is not a pharmaceutical composition. Example 5 is TPM1 overexpression in TREM2−/− mice, which is the opposite of inhibition. The specification does not contain a single example where a TPM1 inhibitor and a TREM2 silencer are both present in a composition administered to a subject. No example corresponds to the claimed invention.
Extensive experimentation would be required: A person of ordinary skill would be required to identify a TREM2 silencer, design sequences, formulate dual-agent ocular delivery, determine dose, determine disease stage, determine whether therapy is beneficial or harmful. That would require extensive screening, animal studies, and dose optimization. Such experimentation would be undue. A person of ordinary skill in the art cannot make a TREM2 silencer without knowing its sequence or cannot determine whether the claimed combination is effective without any data. The specification provides no guidance.
Further, the contrary teachings in applicant’s own incorporated reference create substantial uncertainty. The specification incorporates by reference evidentiary reference Li et al. (TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway. J Neuroinflammation. 2022 Oct 14;19(1):257, hereinafter referred to as "Li"), which is cited in the specification as Li et al., 2022b. A person of ordinary skill in the art would be motivated to consult this reference for further guidance on the TREM2-TPM1 relationship. However, Li teaches findings that directly contradict the therapeutic rationale of the claimed invention.
Li teaches TREM2 knockout increases TPM1 and that TPM1 inhibition in TREM2-deficient retina worsens inflammation. Li establishes that TREM2 acts as a negative regulator, or a "brake," on TPM1-mediated inflammation. This indicates TREM2 normally functions to keep TPM1-driven inflammation in check. When the "brake" (TREM2) is removed, the "accelerator" (TPM1) becomes more active. Therefore, a therapeutic agent designed to silence TREM2 would be predicted to increase TPM1 levels, which is the opposite of inhibition. This directly undermines the logic of the claimed invention, which posits a TPM1 inhibitor that comprises a TREM2 silencer as a beneficial combination. The inventors' foundational research demonstrates that silencing TREM2 disrupts the pathway in a way that both elevates TPM1 and negates the positive effect of a TPM1 inhibitor.
These teachings directly undermine the therapeutic rationale of the claims. A person of ordinary skill would therefore be left uncertain whether administering a TREM2 silencer would improve retinal degeneration, worsen retinal degeneration, depend on disease stage, or depend on retinal disease type. As such, one of skill in the art would logically consult the scientific literature further to resolve this inconsistency.
The independent literature reinforces non-enablement, wherein the weight of independent scientific evidence teaches protective roles for TREM2 in retinal degeneration and indicates that TREM2 silencing would be expected to worsen retinal (see evidentiary references: Bhattacharjee et al. (2016), wherein AMD retinas have NF-kB-mediated upregulation of miRNA-34a resulting in TREM2 down-regulation, reducing phagocytosis. Anti-miRNA-34a restores TREM2. Thus, TREM2 reduction is detrimental, restoring TREM2 is beneficial; Zhou et al., Cell Death Dis. (2024), wherein TREM2-dependent activation of microglia protects photoreceptors via PPARγ and CD36. TREM2 knockout exacerbates photoreceptor death, thus TREM2 deficiency is detrimental and TREM2 activation is protective; Zhou et al., Cell Death Dis. (2023), wherein TREM2 deficiency in microglia accelerates photoreceptor cell death following retinal detachment, thus TREM2 silencing worsens outcomes; He et al., Cell Commun. Signal. (2025), wherein TREM2 regulates microglial migratory responses via type I interferon signaling and TREM2 deficiency impairs migration, phagocytosis, and neuroprotective functions; and Yu et al., J Exp Med. (2024), wherein TREM2 signaling orchestrates microglial migration to atrophic sites and induces galectin-3, TREM2 loss reduces galectin-3, causing phagocytosis defects and worse outcomes, thus TREM2 agonization is protective). The specification does not provide sufficient teaching to overcome this contrary scientific landscape. The present claims do not recite stage-specific administration, chronotherapeutic timing, or late-stage restriction, suggested by the authors own work (evidentiary reference Li R, Zhang J, Wu JM, Fan JQ, Lin B. Temporal biphasic regulation of photoreceptor degeneration by microglial TREM2: A metabolic-immune nexus in retinitis pigmentosa. Sci Adv. 2025 Sep 12;11(37)). Thus, the claims encompass substantial non-enabled embodiments. Accordingly, the claims are rejected for lack of enablement.
The applicant may wish to amend the claims to correspond to the enabled disclosure, for example by limiting the claims to the specific TPM1-targeting siRNA species disclosed in Example 2, a specifically identified TREM2-directed therapeutic agent, and supported formulation, dosing, and disease-stage parameters.
Claim 1, 5-7, and 9-12 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 specification, while being enabling for certain TPM1-directed embodiments, does not reasonably convey to one of ordinary skill in the art that applicant had possession of the claimed subject matter at the time of filing. Independent claim 1 requires “a TPM1 inhibitor … wherein the TPM1 inhibitor comprises a TREM2 silencer.” The specification does not provide adequate written description support for this limitation.
The written description requirement is satisfied only when the disclosure reasonably conveys to those skilled in the art that the inventor had possession of the claimed invention (see Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010)). The specification discloses TPM1 inhibitors and TREM2 perturbation as separate concepts. The specification discloses TPM1 inhibitors and TREM2 genetic knockout, but does not disclose a pharmaceutical composition in which a TPM1 inhibitor comprises a TREM2 silencer.
Example 2 discloses siTPM1 agents (SEQ ID NOS: 17–22) directed to TPM1. These are TPM1-targeting siRNAs. These agents do not target TREM2. Example 4 employs TREM2−/− mice. This is a germline genetic knockout model. This is not a pharmaceutical composition. No therapeutic TREM2 silencing agent is administered. Example 5 teaches TPM1 overexpression in TREM2−/− mice. This is the opposite of TPM1 inhibition. Thus, the specification contains no working example in which a TPM1 inhibitor and a TREM2 silencer are present together in a pharmaceutical composition administered to a subject. Mere recitation (e.g., “in one embodiment, the TPM1 inhibitor includes a TREM2 silencer”) of the claim language does not establish possession.
The specification provides no chemical structure, no nucleic acid sequence, no example, no method of making, no formulation, and no data for any TPM1 inhibitor that comprises a TREM2 silencer. A mere repetition of claim language without disclosure of the claimed species or structure does not satisfy written description (see MPEP § 2163).
No pharmaceutical TREM2 silencer is disclosed. The only TREM2 perturbation disclosed is germline knockout (TREM2−/−). A TREM2 knockout mouse is not equivalent to the claimed pharmaceutical composition. A germline knockout differs materially from pharmaceutical silencing because it involves constitutive deletion from conception, developmental compensation, and whole-organism lifelong absence of TREM2. By contrast, the claims require administration of a pharmaceutical composition to a subject. The specification does not disclose anti-TREM2 siRNA, antisense oligonucleotides, shRNA, miRNA, CRISPR therapeutic constructs, antibodies that silence TREM2, or any pharmaceutical TREM2-silencing agent.
The sequence listing likewise does not remedy this deficiency. SEQ ID NOS. 17-22 are directed to TPM1 and SEQ ID NOS. 11- 12 are PCR primers for Trem2 detection, not therapeutic silencing agents. Accordingly, the specification does not demonstrate possession of a pharmaceutical TREM2 silencer.
The specification also does not disclose either possible interpretation of claim 1. Claim 1 can reasonably be interpreted in two ways. Interpretation 1 would be as a single dual-function agent (i.e., a single molecule that both inhibits TPM1 and silences TREM2). No such molecule is disclosed, exemplified, or described. Interpretation 2 would be as two separate active agents (i.e., a pharmaceutical composition containing a TPM1 inhibitor, and a TREM2 silencer). No such combination is disclosed, formulated, or tested. Accordingly, the specification fails to demonstrate possession under either construction.
The specification’s own mechanistic teachings contradict possession of the claimed combination. The specification repeatedly teaches that TREM2 is upstream and TPM1 is downstream. Li, expressly incorporated by reference in the specification (Li et al., 2022b), teaches TREM2 knockout increased TPM1, TPM1 knockdown in TREM2-deficient retina worsened inflammation, and TPM1 inhibition was beneficial only in TREM2-intact retinas (page 1, Abstract; page 6, “TPM1 knockdown exacerbates inflammation in the TREM2−/− mouse retina”). Thus, the applicant’s own incorporated scientific disclosure teaches that TREM2 silencing elevates TPM1 and TREM2 deficiency renders TPM1 inhibition detrimental. This is directly inconsistent with possession of a therapeutic composition in which a TPM1 inhibitor comprises a TREM2 silencer.
Claim Rejections - 35 USC § 112(b)
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 Applicant regards as his invention.
Claims 1, 5-7, and 9-12 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, regards as the invention.
Claim 1 recites “a TPM1 inhibitor… wherein the TPM1 inhibitor comprises a TREM2 silencer.” This language renders the claim internally inconsistent and indefinite because a “TPM1 inhibitor” is defined functionally as directly inhibiting TPM1 and a “TREM2 silencer” is an upstream regulator, not necessarily a direct TPM1 inhibitor. The claim fails to clarify whether the TREM2 silencer inherently constitutes the TPM1 inhibitor, or TPM1 inhibition is indirect via pathway modulation.
Specifically, it is unclear whether the TREM2 silencer itself is a direct inhibitor of TPM1, the pharmaceutical composition contains two separate active agents, namely a TPM1 inhibitor and a TREM2 silencer, or TPM1 inhibition is achieved indirectly through modulation of upstream TREM2 signaling. The use of the open-ended transitional phrase “comprising” further broadens the ambiguity because claim 1 encompasses both a single dual-function agent that inhibits TPM1 and silences TREM2 and a pharmaceutical composition containing separate TPM1- and TREM2-directed agents. The specification does not define which interpretation is intended.
The uncertainty is heightened by the specification’s own biological disclosures. The specification states that TPM1 mediates inflammation downstream of TREM2, and at that TREM2 regulates TPM1/CREB signaling. Thus, the specification consistently places TREM2 upstream of TPM1 in the relevant signaling pathway. A person of ordinary skill in the art therefore would not understand how a TREM2 silencer, which acts upstream, inherently constitutes a TPM1 inhibitor, which acts downstream. A person of ordinary skill in the art would also question whether a TPM1 inhibitor is even necessary in a composition that silences TREM2, the specification provides no answer.
Moreover, evidentiary reference Li et al., TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway, J. Neuroinflammation 19:257 (2022), expressly cited in the specification as Li et al., 2022b, teaches that TREM2 knockout mouse retinas exhibited increased TPM1 expression (page 6, section “TPM1 knockdown exacerbates inflammation in the TREM2−/− mouse retina,” first paragraph; Additional file 4, Fig. S4A-B). That disclosure indicates that loss or silencing of TREM2 increases TPM1 rather than inhibits TPM1.
Accordingly, one of ordinary skill in the art would not be reasonably apprised of whether a composition containing a TREM2 silencer would inhibit TPM1, increase TPM1, include a separate TPM1 inhibitor, or fall within the scope of claim 1 at all.
Thus, the metes and bounds are unclear as to whether direct inhibition of TPM1 is required, or whether indirect pathway inhibition suffices (see MPEP § 2173.05(e) regarding functional limitations causing ambiguity). Dependent claims 5-7, and 9-12 are included in this rejection because they do not cure the defect noted above.
In addition, claim 9 recites an open-ended list of administration forms connected by "and/or" but fails to specify whether a single form, a combination of forms, or all forms are required. While "and/or" is generally permissible, the lack of clarity regarding whether the composition must be formulated as multiple forms simultaneously (e.g., both an eye drop and an implant and nanoparticle-mediated delivery) renders the scope of the claim ambiguous when read in light of the specification. The specification at recites that the administration form "includes" various forms but does not indicate that all forms are required simultaneously. To overcome this rejection, the applicant should add "wherein" before "the administration form" to properly connect the limitation to claim 6 (as discussed in the objection) and clarify whether the composition is formulated as a single administration form selected from the list or as multiple forms.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. § 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. § 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. § 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 9 is rejected under 35 U.S.C. § 112(d) or pre-AIA 35 U.S.C. § 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 9 recites "the administration form comprises..." without specifying how this limitation further limits the composition of claim 6. Claim 6 recites a pharmaceutical composition that is "barrier delivered through an approach selected from an intravitreal injection, a subretinal injection or a suprachoroidal injection." Claim 9 appears to list additional administration forms (eye drop, eye ointment, hydrogel, etc.). However, it is unclear whether claim 9 is intended to add these forms as additional limitations to the composition of claim 6, replace the delivery approaches of claim 6, or describe separate embodiments. The absence of clear incorporation of claim 6's limitations render the dependent form improper. To overcome this rejection, the applicant should rewrite claim 9 in proper dependent form, wherein the limitation further defines the composition of claim 6.
Claim Rejections - 35 USC § 101
35 U.S.C. § 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 5 are rejected under 35 U.S.C. § 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Claim 1 is drawn to a composition comprising a TPM1 inhibitor that suppresses and/or knocks down the expression and/or activity of the TPM1 for treating retinal degeneration, which is directed at a naturally-occurring product. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception for the following reasons.
With regard to natural products, the MPEP states: “product of nature exceptions includes both naturally occurring products and non-naturally occurring products that lack markedly different characteristics from any naturally occurring counterpart (see, e.g., Ambry Genetics, 11A F.3d at 760, 113 USPQ2d at 1244). Contrary to Myriads argument, it makes no difference that the identified gene sequences are synthetically replicated. As the Supreme Court made clear, neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible. Thus, a synthetic, artificial or non-naturally occurring product such as a cloned organism or a human-made hybrid plant is not automatically eligible because it was created by human ingenuity or intervention (see, e.g. In re Roslin Institute (Edinburgh) 750 F.3d 1333, 1337. 110 USPQ2d 1668, 1671-72 (Fed. Cir. 2014); cloned sheep). Instead, the key to the eligibility of all non-naturally occurring products is whether they possess markedly different characteristics from any naturally occurring counterpart.” (see MPEP 2106.04(b)(II)). The rationale for this determination is explained below by analysis under the Mayo/Alice two-step framework:
Step 1: The claim is directed to a patent-eligible statutory category (i.e., a composition of matter).
Step 2a Prong 1: The claim is directed to a natural phenomenon.
Claim 1 recites a pharmaceutical composition comprising a TPM1 inhibitor, wherein the inhibitor comprises a TREM2 silencer. A “silencer” in this context (e.g., siRNA, miRNA, antisense oligonucleotide) operates by base-pairing to endogenous nucleic acids, harnessing naturally occurring RNA interference (RNAi) machinery (Dicer, RISC complex). The TREM2 silencer does not possess markedly different characteristics from naturally occurring RNAi agents or endogenous regulatory RNAs (e.g., miRNA-21, miRNA-183-5p, and miRNA-107 in the human body inhibit the expression of the TPM1 gene, reducing the amount of the TPM1 protein produced in cells). This inhibition can play a role in the disease process of retinal degeneration (see evidentiary reference: Jiang W, He S, Liu L, Meng X, Lu J, Li J, Chen T, Xu Y, Xiao Q, Qi L, Zhang J. New insights on the role of microRNAs in retinal Müller glial cell function. Br J Ophthalmol. 2024 Feb 21;108(3):329-335, pages 4, figure 4). The human body naturally produces TREM2 and its endogenous regulators. Merely “silencing” it employs a natural mechanism without structural alteration that confers a marked difference from natural counterparts (see MPEP § 2106.04(b)(II), Ambry Genetics, 111 F. Supp. 3d 1108, and In re Roslin Institute, 750 F.3d 1333). The composition of claim 1 does not impart new properties providing distinction from the natural TPM1 inhibitor as a pharmaceutically acceptable addition reads on water, which is also naturally occurring in the body.
Dependent claim 5, as amended reads on water and is, thus now included in the rejection.
Step 2a Prong 2: The claims do not recite additional elements that integrate the exception into a practical application or amount to significantly more than the exception.
The “pharmaceutically acceptable addition” (e.g., excipient, carrier, diluent, solubilizer) of claim 1 and dependent claim 5 is conventional and well-known and reads on water. Adding such carriers to a natural product does not confer patent eligibility (see Funk Brothers Seed Co. v. Kalo Inoculant Co., 333 U.S. 127 (1948)).
The claims merely recite a composition comprising a silencer and generic pharmaceutical additions (e.g., water that is naturally occurring and contained in the human body). These do not meaningfully limit the natural phenomenon.
Step 2b: The claims do not recite additional elements that amount to significantly more than the judicial exception.
With regards to claim 1, the recitation of a composition does not distinguish these claims from the judicial exception. The composition could be a natural product by itself which does not amount to significantly more than the judicial exception. The claim, as a whole, does not recite any additional elements that amount to significantly more than the judicial exception. Specifically, the claim does not include any elements (e.g., recite specific sequence, structure, delivery vector, dosage, or formulation constraints) in addition to the natural product. Thus, the claims read on naturally occurring RNA interference mechanisms. As such, claim 1 and dependent claim 5 are drawn to a judicial exception.
Thus, the claims do not set forth a marked difference in terms of structural and/or or functional differences (properties and/or characteristics) as compared to the naturally-occurring counterpart(s) (see, e.g., Diamond v. Chakrabarty, 447 U.S. 303(1980)). Combining natural products (i.e., the naturally occurring TPM1 inhibitor and water) does not remove the claims from reading upon a judicial selection (Funk Brothers Seed Co. V. Kalo Inoculant Col. 333 U.S. 127 (1948)) because again there is no evidence of a marked difference brought about by combining the instantly claimed materials.
Accordingly, when the relevant factors are analyzed, they weigh against a significant difference between the claimed invention and a judicial exception. Therefore, the claimed invention is not considered to be patent eligible subject matter. The cancellation of claim 4 and incorporation of TREM2 silencer into claim 1 does not cure the § 101 defect. A TREM2 silencer remains a natural phenomenon or product of nature lacking markedly different characteristics from its natural counterpart. The claims do not recite a synthetic, non-naturally occurring molecule with altered structure or significantly different properties.
To overcome this rejection, the applicant may amend the claim to include non-conventional steps of administration, specific dosing regimens, recite a markedly different synthetic compound (e.g., chemically modified oligonucleotide with specific non-natural backbone, altered stability, or cell-penetrating moiety) and provide evidence of markedly different characteristics, or other inventive concepts that would integrate the exception into a practical application rather than a product of nature.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. § 102 and 103 (or as subject to pre-AIA 35 U.S.C. § 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. § 102(b)(2)(C) for any potential 35 U.S.C. § 102(a)(2) prior art against the later invention.
Claims 1 and 5 are rejected under 35 U.S.C. § 103 as being unpatentable over Li, Liang, and Lin (Accumulation of systematic TPM1 mediates inflammation and neuronal remodeling by phosphorylating PKA and regulating the FABP5/NF-κB signaling pathway in the retina of aged mice. Aging Cell. 2022 Mar;21(3):e13566, published electronically 11 Feb 2022, hereinafter referred to as “L3”), in view of Kieffer-Kwon et al. (KSHV MicroRNAs Repress Tropomyosin 1 and Increase Anchorage-Independent Growth and Endothelial Tube Formation. PLoS One. 10(8):e0135560; published 11 Aug 2015, hereinafter referred to as “Kieffer-Kwon”), and in further view of Bhattacharjee et al. (microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration. PLoS One. 2016 Mar 7;11(3):e0150211, hereinafter referred to as “Bhattacharjee”), and Rashid et al. (Microglia in Retinal Degeneration. Front Immunol. 10:1975; published 20 Aug 2019, hereinafter referred to as “Rashid”).
L3 teaches that the actin‐associated protein tropomyosin 1 (TPM1) is a systemic pro‐aging factor associated with elevated inflammatory responses, and structural and functional deficits in aging retinas (i.e., retinal degeneration; page 1, Abstract), which impairs visual function (page 6 and 8, section 2.4), wherein inhibition of TPM1 was shown to counteract age-related dendritic outgrowth and visual function decline in mice (page 8, section 2.5). L3 states that “…TPM1 could be targeted for combating the aging process” (page 1, Abstract) and that “These results suggest therapeutical strategies for attenuating these age‐related retinal defects by targeting TPM1 in old age.” (page 17, second paragraph on the left). Accordingly, L3 teaches that TPM1 is a pathogenic target whose inhibition would have been expected to reduce retinal inflammatory injury and retinal degenerative dysfunction.
Kieffer-Kwon teaches that Kaposi's sarcoma-associated herpesvirus microRNAs, specifically miR-K2 and miR-K5, suppress/inhibit protein expression of tropomyosin 1 (TPM1) (page 1, Abstract). Kieffer-Kwon relates to viral pathogenesis (anchorage-independent growth, endothelial tube formation and although a likely inherent outcome of miRNA inhibition of TPM1, Kieffer-Kwon does not directly and explicitly teach TREM2 silencing nor wherein it is it directed to retinal degeneration.
Bhattacharjee teaches that anti-microRNA-34a (anti-miR-34a) down-regulates TREM2 expression by blocking natural miR-34a in human retinal pigment epithelial (RPE) cells, TREM2 as a phagocytosis-related immune receptor relevant to retinal inflammatory homeostasis (page 1, Title and Abstract), and retinal microglial TREM2 expression in age-related macular degeneration (page 11, first paragraph). Bhattacharjee therefore teaches a TREM2 silencer operative in retinal degenerative tissue. However, Bhattacharjee does not teach TPM1 inhibition.
Rashid explicitly links microglial activation and neuroinflammation to retinal degeneration pathologies, AMD and RP (pages 4-6, " Microglia in Age Related Macular Degeneration" section, reviewed in the entire section and “Microglia in Hereditary Retinopathies” section, first 4 paragraphs, respectively) and that targeting the modulation of microglial activation/inflammation is a promising therapeutic strategy for these diseases (pages 12-13, Conclusion section). Thus, teaching that retinal degeneration is mediated in substantial part by microglial activation, neuroinflammatory signaling, and inflammatory remodeling of retinal tissue. Rashid therefore provides additional motivation to target microglia-associated inflammatory pathways in retinal degenerative disease. However, Rashid does not teach TPM1 inhibition or TREM2 silencing.
The claimed invention differs from the prior art in that no single reference discloses all limitations. L3 teaches TPM1 inhibition for age-related retinal degeneration and Kieffer-Kwon teach TPM1 inhibition, but not in the context of retinal degeneration, and neither L3 or Kieffer-Kwon teach TREM2 silencing. Bhattacharjee teaches TREM2 silencing, but not TPM1 inhibition. Rashid teaches microglial neuroinflammation in retinal degeneration but not TPM1 inhibition or TREM2 silencing. Thus, the differences are the combination of a TPM1 inhibitor that comprises a TREM2 silencer for treating retinal degeneration with conventional pharmaceutically acceptable additions.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to combine the teachings of the prior art references. The motivation to combine arises from the references themselves and from the recognized biological convergence of retinal neuroinflammation. L3 teaches that TPM1 is associated with inflammatory responses, and structural and functional deficits in aging retinas consistent with normal age-related retinal degeneration and resulting functional visual impairments. L3 also teaches the inhibiting TPM1 can counteract age-related indicators of retinal degeneration and visual function decline and directly suggests it’s utility as a therapeutic target for attenuating age‐related retinal defects. One of ordinary skill in the art would expect a TPM1 inhibitor to reduce neuroinflammation, improve visual function, and ameliorate photoreceptor degeneration as taught by L3.
While retinas have a gradual low-level degeneration as a normal part of aging, AMD represents an accelerated or dysregulated version of this degeneration process resulting in more severe visual deficits. Thus, one of ordinary skill in the art, recognizing the teachings of L3 would logically be motivated to apply this teaching to pathological conditions of accelerated retinal degeneration such as AMD (see teachings of Rashid providing the link between microglial inflammation and retinal degeneration in AMD), as this is obvious to try from the teachings of L3 and Rashid. Kieffer-Kwon teaches that TPM1 can be suppressed using miRNAs.
Bhattacharjee teach TREM2 silencing using miRNA-34a and identifies retinal microglial immune signaling as an established pathogenic component of retinal degeneration. A person of ordinary skill in the art would be motivated to apply this known TREM2 silencing tool taught by Bhattacharjee (miR-34a) or other conventional RNAi agents as a predictable application of a known technique to a validated target.
A person of ordinary skill in the art would recognize that both TPM1 and TREM2 are involved in microglial function and inflammation from the teachings of L3 and Bhattacharjee. Bhattacharjee teaches that microglial activation drives retinal degeneration. A person of ordinary skill in the art would be motivated to combine TPM1 inhibition of L3 via the method of Kieffer-Kwon with TREM2 silencing taught by Bhattacharjee to investigate if it would enhance modulation of microglial inflammatory responses. Dual targeting of pathways is a routine and predictable strategy in therapeutic development, wherein combining prior art elements according to known methods is obvious (see MPEP § 2143.01 and KSR, 550 U.S. at 418 (2007)). Further, where prior art provides finite identified therapeutic targets in a known disease pathway, pursuing those targets is ordinarily obvious to try with a reasonable expectation of success (see In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009)).
Rashid provides the link between microglial inflammation and retinal degeneration. Rashid expressly teaches that microglial activation and neuroinflammation drive AMD and RP, and that targeting microglia is a promising therapeutic strategy. A person of ordinary skill in the art would be motivated by Rashid to apply any microglial-modulating therapy, including TREM2 silencing and TPM1 inhibition, to AMD and RP.
Claims 1, 11, and 12 are rejected under 35 U.S.C. § 103 as being unpatentable over Li, Liang, and Lin (Accumulation of systematic TPM1 mediates inflammation and neuronal remodeling by phosphorylating PKA and regulating the FABP5/NF-κB signaling pathway in the retina of aged mice. Aging Cell. 2022 Mar;21(3):e13566, published electronically 11 Feb 2022, hereinafter referred to as “L3”), in view of Kieffer-Kwon et al. (KSHV MicroRNAs Repress Tropomyosin 1 and Increase Anchorage-Independent Growth and Endothelial Tube Formation. PLoS One. 10(8):e0135560; published 11 Aug 2015, hereinafter referred to as “Kieffer-Kwon”), and in further view of Bhattacharjee et al. (microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration. PLoS One. 2016 Mar 7;11(3):e0150211, hereinafter referred to as “Bhattacharjee”), Rashid et al. (Microglia in Retinal Degeneration. Front Immunol. 10:1975; published 20 Aug 2019, hereinafter referred to as “Rashid”), and Santiago et al. (A Drug-Tunable Gene Therapy for Broad-Spectrum Protection against Retinal Degeneration. Mol Ther. 2018 Oct 3;26(10):2407-2417; electronically published 19 Jul 2018, hereinafter referred to as “Santiago”).
L3, Kieffer-Kwon, Bhattacharjee, and Rashid teach the limitations of claim 1, as described above, from which claims 11 and 12 depend, however does not explicitly teach the specific limitations of claims 11 and 12.
Santiago teaches that controlled-release gene therapy (AAV-mediated delivery of CNTF or RPF2) protects photoreceptors from degeneration and rescues visual function in multiple retinal degeneration models (page 1, Abstract and page 5, left column, paragraph 1). Santiago teaches ocular formulations and routes of administration specifically designed for delivery to the retina to treat photoreceptor degeneration (impart photoreceptor protection/"rescuing" photoreceptors) in a controlled-release form (e.g., via trimethoprim administration; Abstract) for sustained therapeutic effect, wherein trimethoprim controls delivered therapeutically delivered transgene (i.e., RPF2) expression in a in a dose-dependent and reversible manner (i.e., trimethoprim withdrawal) (page 1, last paragraph) by delivery of the therapeutic agent to the subretinal space via the vitreous humor by intravitreal injection (page 2, left column, paragraph 1; page 8, left column, paragraph 2). However, Santiago does not explicitly teach TPM1 inhibition or TREM2 silencing.
Thus, the differences are the combination of a TPM1 inhibitor that comprises a TREM2 silencer for treating retinal degeneration with conventional pharmaceutically acceptable additions which is addressed by the combination of L3, Kieffer-Kwon, Bhattacharjee, and Rashid, as discussed above, to reduce neuroinflammation and rescue photoreceptor degeneration and visual function. Santiago teaches visual function rescue. Santiago teaches that visual function rescue is an achievable goal. Santiago teaches that therapeutic interventions can rescue photoreceptors and preserve visual function in retinal degeneration models.
A person of ordinary skill in the art would be motivated to evaluate whether TREM2 silencing and TPM1 inhibition achieve these same well-recognized therapeutic endpoints. The claimed functional results of reducing neuroinflammation, rescuing photoreceptor degeneration and visual function is the predictable outcome of successfully treating the underlying pathology. A skilled artisan would have had a reasonable expectation of success in combining these teachings because retinal inflammation and microglial signaling were well-established therapeutic targets at the relevant filing date, intraocular therapeutic delivery for retinal disease was routine, and modulation of retinal inflammatory pathways had already been shown to alter retinal degenerative phenotypes. The combination therefore required ordinary optimization of known retinal therapeutic variables rather than unpredictable biological innovation.
Claims 1, 6, 7 and 9 are rejected under 35 U.S.C. § 103 as being unpatentable over Li, Liang, and Lin (Accumulation of systematic TPM1 mediates inflammation and neuronal remodeling by phosphorylating PKA and regulating the FABP5/NF-κB signaling pathway in the retina of aged mice. Aging Cell. 2022 Mar;21(3):e13566, published electronically 11 Feb 2022, hereinafter referred to as “L3”), in view of Kieffer-Kwon et al. (KSHV MicroRNAs Repress Tropomyosin 1 and Increase Anchorage-Independent Growth and Endothelial Tube Formation. PLoS One. 10(8):e0135560; published 11 Aug 2015, hereinafter referred to as “Kieffer-Kwon”), and in further view of Bhattacharjee et al. (microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration. PLoS One. 2016 Mar 7;11(3):e0150211, hereinafter referred to as “Bhattacharjee”), Rashid et al. (Microglia in Retinal Degeneration. Front Immunol. 10:1975; published 20 Aug 2019, hereinafter referred to as “Rashid”), Irigoyen et al. (Subretinal Injection Techniques for Retinal Disease: A Review. J Clin Med. 11(16):4717; published 12 Aug 2022, hereinafter referred to as “Irigoyen”), and Santiago et al. (A Drug-Tunable Gene Therapy for Broad-Spectrum Protection against Retinal Degeneration. Mol Ther. 2018 Oct 3;26(10):2407-2417; electronically published 19 Jul 2018, hereinafter referred to as “Santiago”).
L3, Kieffer-Kwon, Bhattacharjee, and Rashid teach the limitations of claim 1, as described above, from which claims 6, 7 and 9 depend, however do not teach specific limitations of claims 6, 7, and 9. More specifically, while Li and Rashid provide the motivation to use a TPM1 inhibitor for retinal degeneration, they do not explicitly detail the formulation for all of the methods and forms of ocular delivery, as limited by the claims.
Irigoyen teaches the use of transcorneal subretinal injections as of method of delivery to the subretinal space (page 6, paragraph 5) in the context of therapeutic delivery for diseases affecting photoreceptors as a means for improving visual function (page 1, Abstract), providing context for transcorneal forms of administration for delivery to a subject’s subretinal space.
Santiago teaches ocular formulations and routes of administration specifically designed for delivery to the retina to treat photoreceptor degeneration (impart photoreceptor protection/"rescuing" photoreceptors) in a controlled-release form (e.g., via trimethoprim administration; Abstract) for sustained therapeutic effect, wherein trimethoprim controls delivered therapeutically delivered transgene (i.e., RPF2) expression in a in a dose-dependent and reversible manner (i.e., trimethoprim withdrawal) (page 1, last paragraph) by delivery of the therapeutic agent to the subretinal space via the vitreous humor by intravitreal injection (page 2, left column, paragraph 1; page 8, left column, paragraph 2).
While neither reference specifically teaches TPM1 inhibitors or TREM2 silencers, they provide context of controlled-release therapeutic ocular delivery forms, intravitreal subretinal route of administration and indication for treatment of retinal degeneration (such as AMD and RP), as well as transcorneal subretinal routes of administration. Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to formulate the TPM1 inhibitor composition, which is motivated by Li and Rashid, using the standard ocular drug delivery formulations and routes of administration taught by Santiago and/or Irigoyen to effectively deliver the therapeutic to the site of action in the retina with a reasonable expectation of success.
The claimed routes and forms are all known in the ocular drug delivery and retinal therapy fields. For example, injections (intravitreal/subretinal) are standard of care for retinal disease and hydrogel, implant, nanoparticle etc. are known in ocular delivery literature. The application of these known forms to a TPM1 inhibitor composition is obvious given the prior art teaching ocular delivery to retina by Santiago and Irigoyen plus conventional delivery forms. One would be motivated to make the formulation and administration choices form those limited by the claims because these methods of administration and forms are known in the art for the same purpose of delivering pharmaceutical ocular therapeutics to a patient in need of treatment for an ocular condition or disease state.
The combination of L3, Kieffer-Kwon, Bhattacharjee, and Rashid teach the TPM1 inhibitor and TREM2 silencer and retinal degeneration with conventional pharmaceutically acceptable additions, as discussed above, Santiago teaches reduced neuroinflammation to rescue photoreceptor degeneration and visual function, as discussed above, and using specific ocular delivery routes and formulations. Santiago teaches controlled-release ocular delivery and Irigoyen teaches ocular injection routes. A person of ordinary skill in the art would be motivated to formulate any ophthalmic therapeutic, including a TPM1 inhibitor/TREM2 silencer composition, using these known delivery routes, as this is nothing more than the application of conventional techniques to a new therapeutic agent.
Response to Arguments
Applicant Arguments/Remarks of the reply, filed 25 March 2026, have been fully considered.
Regarding the rejections under 35 U.S.C. § 101, the claimed composition in instant claim 1 comprises a TPM1 inhibitor, wherein the TPM1 inhibitor comprises a TREM2 silencer. The examiner has very carefully considered this matter previously for claim 1, and here again thoroughly as amended, to determine whether this composition is "markedly different" from any naturally occurring counterpart. The specification and the cited prior art identify the following natural counterparts including endogenous TREM2 silencers (e.g., naturally occurring miRNAs such as miR-34a that down-regulate TREM2 expression as taught by Bhattacharjee and Shi), endogenous TPM1 inhibitors (naturally occurring miRNAs such as miR-21, miR-183-5p, miR-107 that suppress TPM1 expression as cited in the prior Office Correspondence), the TREM2 protein itself (naturally occurring transmembrane receptor as NCBI Reference Sequence NP_061838.1; https://www.ncbi.nlm.nih.gov/protein/NP_061838.1), the TPM1 protein itself (naturally occurring cytoskeletal protein as NCBI Reference Sequence NP_000357.3; https://www.ncbi.nlm.nih.gov/protein/NP_000357.3).
The claimed composition is a synthetic combination of a TPM1 inhibitor and a TREM2 silencer. The relevant natural counterpart is not a single molecule but rather the natural occurrence of TPM1 inhibitors and TREM2 silencers as separate entities in the human body. The claim does not specify any sufficient structural differences, wherein the TPM1 inhibitor identity is unspecified and could be natural miRNA, synthetic siRNA, antisense oligonucleotide, etc. The claim permits naturally occurring miRNAs (e.g., miR-21, miR-183-5p, miR-107). The TREM2 silencer identity is also unspecified and could be naturally occurring miR-34a (Bhattacharjee) or other. The claim permits natural miR-34a. Claim 1 does not recite any chemical modifications, thus the claim permits unmodified natural RNA (e.g., ribose, phosphodiester bonds, unmodified bases).
The TPM1 inhibitors and TREM2 silencers exist separately in nature, not as a single combined composition comprising both as in amended claim 1, which was conscientiously considered by the examiner. However, the combination of the TPM1 inhibitor and TREM2 silencer is a formulation, not a structural modification of the agents themselves. The claim does not require any structural modification to the TPM1 inhibitor or the TREM2 silencer. Amended claim 1 permits a composition comprising the naturally occurring miR-21 as a TPM1 inhibitor and naturally occurring miR-34a as a TREM2 silencer in a saline solution as a pharmaceutically acceptable addition.
The functional differences of the composition of claim 1 and the natural counterparts are insufficient. The TPM1 inhibitor of claim 1 inhibits TPM1 and natural miRNAs inhibit TPM1, thus provide an identical function. The TREM2 silencer of claim 1 silences TREM2 and natural miR-34a silences TREM2, thus provide an identical function. In claim 1, consideration of a therapeutic effect is not applicable as the natural agents are not administered for therapy. The intent to use the composition for treating retinal degeneration is not a functional difference in the composition itself. The addition of a "pharmaceutically acceptable addition" (e.g., saline, water) does not alter the fundamental functions of the active agents.
In addition, a review of the specification reveals no evidence that the claimed TPM1 inhibitor or TREM2 silencer has markedly different characteristics from natural counterparts. Example 2 (siTPM1) shows synthetic siRNAs with 3' modifications (SEQ ID NOS: 17-24), however, claims 1 and 10-12 do not require these modifications. The claims cover any TPM1 inhibitor, including natural miRNAs. Example 4 (TREM2 knockout) is as genetic knockout, not a composition and is not relevant to the composition claim 1 or the methods administering the composition in claims 10-12. Bhattacharjee teaches naturally occurring miR-34a silences TREM2 with no structural modification and Kieffer-Kwon taches naturally occurring KSHV miRNAs suppress TPM1 (KSHV miRNAs of viral origin are natural). The specification does not identify any specific structural modification (e.g., 2'-O-methyl, phosphorothioate backbone, locked nucleic acid, cholesterol conjugation) that would render the claimed TREM2 silencer or TPM1 inhibitor markedly different from naturally occurring RNAs. Even if such were present in the specification, it is not claimed as such in claim 1.
Moreover, the examiner has considered comparison of the composition of instant claim 1 to patent eligible and ineligible products. In the case of Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013), cDNA is patent eligible because it is markedly different by lacking introns, and thus is a non-natural sequence. However, isolated natural DNA is patent ineligible because it is not markedly different because it is structurally identical to natural DNA. In Diamond v. Chakrabarty, 447 U.S. 303 (1980), genetically engineered bacterium is patent eligible because it is markedly different and introduces new properties not found in nature. In Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 131 (1948), the combination of two natural miRNAs is patent ineligible because it introduces no new properties and is just a mixture and natural miRNA in saline is also patent ineligible because it is not markedly different and has the same structure, same function. Furthermore, the discovery of a natural phenomenon cannot be patented, which applies to claims 10-12 that depend from claim 1, which add the limitation of administering the composition to obtain merely the natural functional outcome of application of the natural composition.
Accordingly, the claimed composition falls into the ineligible category because the individual active agents, as currently claimed, may be natural products (miRNAs), the combination does not create a new property beyond the sum of the individual functions, and the pharmaceutically acceptable addition (carrier) is conventional. If claim 1 were allowed, it would preempt the use of any TPM1 inhibitor that comprises a TREM2 silencer for treating retinal degeneration, regardless of whether the agents are natural miRNAs, synthetic siRNAs, or other modalities.
In summary, natural counterpart exists that inhibit TPM1 and silence TREM2, no structural difference exists from the claimed composition to that of natural RNA sequences (e.g., does not require any structural modification), no functional difference exists as both natural and the composition of claim 1 have the same functions of TPM1 inhibition and TREM2 silencing, and the combination of two natural products with conventional carrier, as in claims 1 and 5, is not markedly different under Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 131 (1948). The claim encompasses unmodified naturally occurring RNA molecules as the TPM1 inhibitor and TREM2 silencer, and the combination with a pharmaceutically acceptable addition does not confer markedly different characteristics.
Regarding the rejection of claim 1 under 35 U.S.C. § 102 as anticipated by Kieffer-Kwon, Kieffer-Kwon discloses Kaposi’s sarcoma-associated herpesvirus (KSHV) microRNAs (miR-K2, miR-K5) that suppress/inhibit TPM1 expression (Abstract, page 1). The reference teaches live endothelial cells containing these miRNAs inherently contain the conventional excipient water (i.e., a pharmaceutically acceptable addition). Thus, Kieffer-Kwon discloses a composition comprising a TPM1 inhibitor (KSHV miRNA) and a pharmaceutically acceptable addition (water). Wherein, the “for treating” limitation is a statement of intended use that does not impart patentable weight (see In re Schreiber, 128 F.3d 1473, 1478 (Fed. Cir. 1997).
The applicant argues that Kieffer-Kwon does not disclose a “TREM2 silencer”. However, claim 1 does not require the TPM1 inhibitor to be exclusively a TREM2 silencer, rather it requires that the TPM1 inhibitor comprises a TREM2 silencer. Kieffer-Kwon’s composition (KSHV miRNAs + water) is within the literal scope of the claim because it is a TPM1 inhibitor that suppress TPM1 expression and the claim does not require any specific mechanism distinguishing TREM2-mediated suppression from direct suppression.
The claimed “TREM2 silencer” is functionally defined and the claim does not exclude microRNAs that indirectly influence TPM1 via upstream pathways. Thus, the prior art microRNAs reasonably read on the claimed inhibitor. The applicant has not shown that Kieffer-Kwon’s composition cannot comprise a TREM2 silencer, as the claim is open-ended with the use of “comprising”. Additionally, the “pharmaceutically acceptable addition” remains broad enough to encompass inherent cellular components. However, based on the amendment to claim 1, the rejection of claim 1 under 35 U.S.C. § 102 has been withdrawn and the claim is now rejected under 35 U.S.C. § 103 to include an additional prior art reference the explicitly teaches TREM2 silencing.
The applicant also argues that Kieffer-Kwon relates to viral pathogenesis, not retinal degeneration. This argument is irrelevant. Anticipation requires only that each claim limitation appears in a single prior art reference, either expressly or inherently. Kieffer-Kwon discloses a TPM1 inhibitor composition. The “for treating” limitation is not limiting as to composition claims. The composition of Kieffer-Kwon is structurally identical to a TPM1 inhibitor composition and the new use for retinal degeneration does not create a new composition or patentably distinguish the composition.
Regarding the prior 35 U.S.C. § 103 rejections of claims 1, 5-7, and 9-12, the applicant argues that Li is not prior art due to § 1.130(a) declaration. Accordingly, the rejections have been withdrawn.
The applicant argues that Rashid, Santiago and Irigoyen do not disclose targeting TPM1. However, obviousness does not require each reference to disclose every limitation. The combination of prior art teaching TPM1 and TREM2 targeting with Rashid (AMD/RP involve microglial inflammation) with Santiago (rescue of visual function) and with Irigoyen (ocular delivery) renders the claimed composition and methods obvious (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007)). Inflammation pathways are routinely targeted. Selection of pathway nodes is obvious to try.
Regarding the new 35 U.S.C. § 103 rejections for claims 1, 5-7, and 9-12, excluding the Li prior art reference, as set forth above, the newly cited L3 reference above was electronically published 11 February 2022, which is approximately 15 months and 10 days from the earliest effective filing date of the instant application (21 May 2023). Thus, the L3 disclosure was made more than one year before the earliest effective filing date. As a result, the L3 disclosure does not meet the temporal requirement for the grace period exception under 35 U.S.C. § 102(b)(1). Thus, the 11 February 2022 publication date stands as prior art under 35 U.S.C. § 102(a)(1).
If the applicant wishes to advance prosecution, amendments should focus on structural limitations (e.g., specific nucleic acid sequences), non-conventional delivery systems, and demonstrated unexpected results tied to TREM2-specific modulation, to the extent they are supported in the originally-filed disclosure. Otherwise, the claims remain unpatentable over the prior art and under the statutory requirements.
Conclusion
No claims are allowed.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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