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 .
Claims 1, 4, 6-10, 17 and 20-23 are pending. Claims 6-10 are withdrawn from consideration as being drawn to a nonelected invention.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10 September 2025 has been entered.
Status of the Application
Applicant’s response and amendment filed 10 September 2025 are acknowledged and entered.
Applicant has amended no claim; cancelled Claims 11-14 and 18-19; and added Claims 20-23.
Election/Restrictions
Newly submitted Claim 23 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: despite that the instant Spec. (¶33) and Claim 23 (by incorporating all limitations from Claim 1) recites that all OM-174 a TLR antagonist, a search of the art indicates that OM-174 is in fact a TLR2 agonist that activates—instead of inhibits—TLR2. See Yu (et al. 2010. Toll-like receptors 2/4 agonists: a potential strategy for preventing invasion and metastasis of hepatocellular carcinoma. Gut 59[10]:1447-1448, “Yu”), specifically §Main text ¶4:
OM-174 is … an agonist of TLR 2/4 and can induce the expression of iNOS and a variety of proinflammatory cytokines/chemokines, including tumour necrosis factor α (TNFα), interferon γ (IFNγ), interleukin 8 (IL8), IL10 and IL23. [emphasis added]
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, Claim 23 is withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03. Note that, in the absence of evidence indicating otherwise, Yu’s teaching that OM-174 agonizes TLR2, thereby promoting inflammation, indicates that the invention of Claim 23 (a method of treating AMD) would not be enabled.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Response to Amendment
Applicant has amended the Spec. to overcome Objections; the objections are withdrawn.
Applicant has amended the Spec. to overcome Objections to the Drawings; the objections are withdrawn.
Applicant has amended Claim 1 to overcome the 112(a) written description rejection; the 112(a) written description rejection is not withdrawn.
The 102 rejection over Feng is maintained.
The 103 rejections are maintained.
Claims 1, 4, 17, and 20-22 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Claim Interpretation
Claim 1 recites: A method of treating age-related macular degeneration in a subject in need thereof, the method comprising the step of administering a pharmaceutically effective amount of an antagonist of a TLR to the RPE of the subject to decrease the expression or activation of a toll-like receptor in the subject and so treat AMD in the subject, wherein the TLR is TLR2. The claim is interpreted as “to decrease” goes with both “expression” and “activation”; i.e., the method step requires either 1) the antagonist produces the outcome of decreasing expression of TLR2 or 2) the antagonist produces the outcome of decreasing activation of TLR2.
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, 4, 17, and 21 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. This is a written description rejection. This rejection is maintained and updated in view of the claim amendments.
Claims 1, 4, 17, and 21 recite a method of treating age-related macular degeneration (AMD) in a subject in need thereof, the method comprising the step of administering a pharmaceutically effective amount of an antagonist of a toll-like receptor TLR to the retinal pigment epithelium of the subject to decrease the expression or activation of the TLR and so treat AMD in the subject and wherein the TLR is TLR2 (Claim 1); and wherein the TLR2 antagonist is a TLR2 antagonist antibody (Ab) or a TLR2 antagonist Ab fragment (Claim 21).
The method requires administration of some kind of TLR2 antagonist that decreases expression or decreases activation of TLR2, and, for Claim 21, any kind of TLR2 antagonist Ab or fragment of a TLR2 antagonist Ab.
These broad claims encompass a large genus of TLR2 antagonists, and the sub-genera of TLR2 antagonist Abs and fragments of any TLR2 antagonist Abs.
Any kind of agent TLR2 antagonist that decreases expression or decreases activation of TLR2 would be encompassed by the claims as instantly presented. Any kind of TLR2 antagonist Abs, and fragments of any TLR2 antagonist Abs would be encompassed by the claims as instantly presented.
In each case, the agents are defined solely by their function. No structure or partial structure that is responsible for the TLR2-antagonizing has been described. Note that Watson (et al. 2017. The individual and population genetics of antibody immunity. Trend. Immunol. 38[7]:459-470, “Watson”) teaches (§The Molecular Basis for Antibody Diversity, entire §) Abs are incredibly diverse because Ab production involves hypermutation.
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
The potential TLR2 antagonists are described on Spec. ¶15-35. Those § of the Spec. disclose broad categories or “genera” of TLR antagonists as well as subgenera that fall into these categories (e.g., small molecule TLR antagonists and immunoglobulin TLR antagonists). Those § of the Spec. disclose broad categories or “genera” of decreasers of TLR expression as well as subgenera that fall into these categories (e.g., aptamers and siRNA). These are broad subgenera with diverse members and different structures that underlie their functions. When it comes to antagonist Abs or fragments of antagonist Abs, the Spec. teaches (¶31) the Ab can be a murine or human Ab or fragment of an Ab. The Spec. teaches that (¶30) candesartan cilexetil (“Atacand®”) is a TLR small molecule antagonist; (¶32) OPN-305/Tomaralimab and T2.5 are immunoglobulin TLR antagonists; and (¶33) OM-174 is a lipid-A analogue TLR antagonist. Atacand® can be considered a chemical compound TLR antagonist. Each of those TLR antagonists works to inhibit TLR2 or its activation. Note that although the Spec. discloses that OM-174 is a TLR antagonist, Yu (et al. 2010. Toll-like receptors 2/4 agonists: a potential strategy for preventing invasion and metastasis of hepatocellular carcinoma. Gut 59[10]:1447-1448, “Yu”) describes that OM-174 is a TLR2 agonist, not antagonist (see §Election/Restriction).
The specification teaches the following examples of the methods used to decrease expression or decrease activation of TLR2:
Example 1 (¶95; Fig. 1) demonstrates TLR2 activation induces AP complement factor expression in monocytes, macrophages, and the RPE. Example 2 (¶96; Fig. 1) demonstrates retinal cells generate complement factors in response to TLR2 activation and oxidative stress product CEP. Example 3 (¶97; Fig. 2) teaches inhibiting TLR2 protected cells from oxidative stress-induced photoreceptor loss in vitro, that TLR2 activation drives C3 deposition, and that absence of Mal and MyD88 in cells reduced induction of C3 and CFB (i.e., deposits associated with AMD). Example 4 (¶98; Figs. 10, 11, 12) teaches NaIO3 produces a mouse model of oxidative stress. Examples 5-10 (¶99-104; Figs. 3-6) teach NaIO3 induces less RPE damage in a TLR2 -/- mouse vs WT control, and investigate some of the mechanisms underlying that difference in mice and in cells. Example 8 (¶102, Fig. 5) discusses treating cells in the presence of a monoclonal neutralizing anti-TLR2-Ab which attenuated the number of MAC formations. Example 11 demonstrates that (¶105; Fig. 7) anti-TLR2 therapy protects against oxidative stress/RPE degeneration/photoreceptor cell death in an NaIO3-induced mouse model.
Some of those examples use TLR2 KO mice, but that is not a viable method of decreasing expression of TLR2 to treat AMD in a subject, and does not comprise a method step that can be carried out in a subject because nothing is administered. None of those examples teaches about decreasing expression/activation of any TLR2 with anything other than T2.5 (i.e., ¶89, AB_763722) or AB_302428. None of those examples demonstrates treating AMD by decreasing activation of TLR2 with anything besides T2.5 or AB_302428. In all cases, one of those two anti-TLR2 antibodies was injected to the eye.
Regarding fragments of Abs, none of the examples discusses or describes treating AMD with any anti-TLR2 Ab fragment. Nor does the Spec. describe any requisite structure of an anti-TLR2 Ab fragment that performs the function of antagonizing TLR2. For those reasons an artisan would not know whether any given Ab or fragment of an anti-TLR2 Ab can be used in the claimed method. An artisan would not know how much of an anti-TLR2 Ab is necessary to carry out the function of antagonizing TLR2 to decrease its expression and/or decrease its activation.
The Spec. teaches that (Table 1) two anti-TLR2 antibodies were used as the agents to decrease activation of TLR2. The antibody registry (antibodyregistry.org. “AB_302428” and “AB_763722”/T2.5. Accessed 30 May 2024, of record) teaches that AB_302428 is a polyclonal antibody and AB_763722 is a monoclonal antibody. Based on the definitions of the different kinds of antagonists discussed above in §Claim interpretation, the TLR2 antibodies can be considered competitive, reversible, selective (monoclonal Ab), nonselective (polyclonal Ab), and immunoglobulin.
The Specification provides no evidence of treating AMD by using any agent that decreases expression of TLR2. The Spec. does not show exemplary members of the broad genus of any agent that decreases expression/activation of TLR2—aside from the two examples of anti-TLR2 neutralizing antibodies. The Spec. does not show exemplary members of the sub-genera of claimed agents or antagonists: anti-TLR2 Abs or fragments of anti-TLR2 Abs. Applicant has identified agents that decrease TLR2 expression and all the various kinds of anti-TLR2 antagonist Abs (and fragments of them) encompassed by the claims, but tested only two kinds of anti-TLR2 antibodies which work by decreasing TLR2 activation. Even so, the two anti-TLR2 antibodies are two species in a single subgenus (i.e., decreasers of TLR2 activation) and do not demonstrate possession of all decreasers of TLR2 activation, which is the broad sub-genus claimed or all decreasers of TLR2 expression which is another sub-genus claimed. Applicant has used KO mutants to reduce TLR2 and anti-TLR2 antibodies to decrease TLR2 activation. Although these experiments demonstrate that TLR2 is involved in AMD and that inhibiting TLR2 with the two species of anti-TLR2 antibodies can reduce photoreceptor cell death to treat AMD, the examples do not provide support for decreasing activation or expression of TLR2 to treat AMD because the examples show only individual species. The examples do not provide support for using a fragment of an anti-TLR2 Ab to attain the claimed outcome of treating AMD. The Specification does not provide sufficient evidence that their methods would work with the entire genus of any decreasers of expression of TLR2, or any decreasers of expression/activation of TLR2. The Specification does not provide specific guidance for determining which species of decreasers of TLR2 expression/activation within the broad genus would or would not be acceptable to treat AMD, or which species of anti-TLR2 Abs or what fragments of anti-TLR2 Abs would or would not be acceptable. Although the Claims claim a functional characteristic (i.e., the step of decreasing expression/activation of TLR2), the functional characteristic is not coupled with a known structure.
Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for decreasing expression/activation of TLR2. Among the evidences provided for decreasing expression/activation of TLR2, no core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for the decreasing expression/activation is disclosed in such a way to demonstrate possession of the full invention as claimed at time of filing. The methods of decreasing expression that are conditions (i.e., the KO mutations) lack a common structure. Sufficient data are not shown to substantiate claiming the broad subgenus of decreasers of TLR2 expression/activation. There is also no structure shared by, for example, small molecules and immunoglobulin antagonists and siRNA, which have different modes of action. There are many ways of decreasing expression and decreasing activation, and the Specification does not teach any defining characteristics of such decreasing. There are many ways an anti-TLR2 Ab can be split into “fragments” and the Spec. does not describe any particular structure that is responsible for the antagonist function of the Ab.
The specification teaches only a couple members from some of the genera or sub-genera, namely the anti-TLR2 antibodies (for which data are shown) and the decreasers of TLR2 activation Atacand®, OPN-305/Tomaralimab, T2.5, and OM-174 (for which no data are shown). However the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge subgenus of decreasers of TLR2 expression/activation or anti-TLR2 Abs or fragments of anti-TLR2 Abs claimed.
While none of these elements is specifically required to demonstrate possession, in combination their lack means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of an invention methods of treating AMD by administering the broad subgenus decreasers of TLR2 expression and decreasers of TLR2 activation. Claims 1 and 21 are rejected for failing to demonstrate possession of the claimed invention. Claims 4, 17, and 21 are rejected because they depend from Claim 1 and do not remedy the issues. Claims 20 and 22 recite specific TLR2 antagonists—and therefore remedy the issues with Claim 1—so they are not included in this rejection.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 17, and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Feng (et al. 2017. A Proinflammatory Function of Toll-Like Receptor 2 in the Retinal Pigment Epithelium as a Novel Target for Reducing Choroidal Neovascularization in Age-Related Macular Degeneration. Am. J. Pathol. 187[10]:2208-2221; “Feng”, of record). This rejection is updated in response to the claim amendments.
Feng is drawn to TLR2’s proinflammatory function in AMD. Feng teaches (§Abstract) choroidal neovascularization (CNV) is a major cause of blindness for AMD patients and inhibiting TLR2 treated CNV: TLR2 antagonism effectively suppressed initiation and growth of spontaneous choroidal neovascularization in a mouse model. Feng teaches (§Introduction ¶4) their studies indicate dysregulated TLR2 activation functions in CNV pathogenesis and these studies point to the TLR2 pathway as a potential therapeutic target to prevent blindness in patients with AMD.
Note that Claim 1 recites simply a method of treating age-related AMD in a subject in need thereof, the method comprising the step of administering a pharmaceutically effective amount of an antagonist of TLR2 to the retinal pigment epithelium of the subject to decrease expression or activation of the TLR2 in the subject and so treat age-related AMD in the subject. Nothing about that claim requires that the AMD be dry AMD. Since Feng teaches antagonizing TLR2 to suppress CNV and teaches this pathway as a therapeutic target for preventing blindness in patients with AMD, Feng teaches that inhibiting TLR2 would treat AMD (i.e., by preventing blindness). Therefore Feng anticipates Claim 1.
Feng teaches that (§Discussion, final¶) because TLR2 is highly localized on the apical surface of RPE, ocular delivery of TLR2 antagonist could be an effective route of delivery. Therefore Feng teaches administering the TLR2 antagonist to the RPE. Feng teaches (§Introduction ¶3) increased TLR2 expression and reactivity in peripheral blood mononuclear cells from patients with AMD support the concept that TLR2 may be involved in disease pathogenesis. Since Feng teaches delivering the TLR2 antagonist to the site of TLR2 protein and also teaches that TLR2 expression and reactivity is increased in peripheral blood mononuclear cells from patients with AMD, Feng teaches administering the TLR2 antagonist to mononuclear cells which includes mononuclear phagocytes. Therefore Feng anticipates Claim 17.
Feng teaches (§Materials and Methods-Treatment of Spontaneous CNV in JR5558 Mice) they used a purified mouse neutralizing anti-mouse TLR2 antibody from InvivoGen: JR5558 mice,39e41 which spontaneously generate CNV lesions, were treated with a single intravitreal injection (in 0.8 mL) of… purified mouse neutralizing anti-mouse TLR2 antibody (0.8, 1.6, or 3.2 mg per injection; mab-mTLR2; InvivoGen, San Diego, CA). That teaches that the JR5558 mouse is a model of CNV which is an outcome of AMD. That teaches that the mice were treated with a single intravitreal injection. The notation of the antibody indicates it’s a monoclonal antibody. Therefore the neutralizing anti-TLR2 antibody of Feng is a competitive TLR antagonist, a reversible TLR antagonist, a selective TLR antagonist, and an immunoglobulin TLR antagonist. Therefore Feng also anticipates Claim 21.
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.
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.
Claim(s) 1, 4, 17, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Feng (et al. 2017. A Proinflammatory Function of Toll-Like Receptor 2 in the Retinal Pigment Epithelium as a Novel Target for Reducing Choroidal Neovascularization in Age-Related Macular Degeneration. Am. J. Pathol. 187[10]:2208-2221; “Feng”, of record) as evidenced by Encyclopedia Britannica (2020. “Phagocyte”. Available online at Britannica.com. Accessed 30 May 2024; “Encyclopedia”, of record), and Doyle (et al. 2018. TLR2 bridges oxidative damage and complement-associated pathology and is a therapeutic target for age-related macular degeneration. Invest. Ophthalmol. Visual Sci. 59:3475; “Doyle”, of record). This rejection is updated in response to the claim amendments.
Feng is drawn to TLR2’s proinflammatory function in AMD. Feng teaches (§Abstract) choroidal neovascularization (CNV) is a major cause of blindness for AMD patients and inhibiting TLR2 treated CNV: TLR2 antagonism effectively suppressed initiation and growth of spontaneous choroidal neovascularization in a mouse model. Feng teaches (§Introduction ¶4) their studies indicate dysregulated TLR2 activation functions in CNV pathogenesis and these studies point to the TLR2 pathway as a potential therapeutic target to prevent blindness in patients with AMD. Feng teaches a mechanism by which TLR2 treats AMD: Feng found that (Fig. 7B; §End Products of Lipid Oxidation Enhance TLR2-Mediated Expression of Proinflammatory Genes in RPE) administering the compound CEP plus Pam2CSK4 increased TLR2 expression, but that administering the anti-TLR2 antibody decreased TLR2 expression. Feng teaches that (same §; Fig. 8) proinflammatory ligands including the products of lipid oxidation enhance TLR2 activation but that using a neutralizing anti-TLR2 antibody suppressed activation of proinflammatory genes.
Note that Claim 1 recites simply a method of treating age-related AMD in a subject in need thereof, the method comprising the step of administering a pharmaceutically effective amount of an antagonist of TLR2 to the retinal pigment epithelium of the subject to decrease expression or activation of the TLR2 in the subject and so treat age-related AMD in the subject. Nothing about that claim requires that the AMD be dry AMD. Since Feng teaches antagonizing TLR2 with a neutralizing antibody to suppress CNV and teaches this pathway as a therapeutic target for preventing blindness in patients with AMD, Feng teaches that inhibiting TLR2 would treat AMD (i.e., by preventing blindness). Therefore Feng teaches the limitations of Claim 1.
Regarding Claim 21: Feng teaches (§Materials and Methods-Treatment of Spontaneous CNV in JR5558 Mice) they used a purified mouse neutralizing anti-mouse TLR2 antibody from InvivoGen: JR5558 mice,39e41 which spontaneously generate CNV lesions, were treated with a single intravitreal injection (in 0.8 mL) of… purified mouse neutralizing anti-mouse TLR2 antibody (0.8, 1.6, or 3.2 mg per injection; mab-mTLR2; InvivoGen, San Diego, CA). That teaches that the JR5558 mouse is a model of CNV which is an outcome of AMD. That teaches that the mice were treated with a single intravitreal injection. The notation of the antibody indicates it’s a monoclonal antibody. Therefore the neutralizing anti-TLR2 antibody of Feng is a competitive TLR antagonist, a reversible TLR antagonist, a selective TLR antagonist, and an immunoglobulin TLR antagonist. Therefore Feng also teaches the limitations of Claim 21.
Feng teaches that (§Discussion, final¶) because TLR2 is highly localized on the apical surface of RPE, ocular delivery of TLR2 antagonist could be an effective route of delivery. Feng teaches (§TLR2 Is Highly Expressed by the RPE in Human Eyes with and without AMD) RPE cells normally express TLR2 and continue to do so at all stages of AMD: RPE cells normally express high levels of TLR2 and that the RPE continue to express TLR2 at different stages of AMD. Feng teaches (§Introduction ¶3) increased TLR2 expression and reactivity in peripheral blood mononuclear cells from patients with AMD support the concept that TLR2 may be involved in disease pathogenesis. Feng teaches (§TLR2 Is Highly Expressed by the RPE in Mouse Eyes with and without CNV; Fig. 3) they detected TLR2 protein in cells tightly associated with CNV vessels, including leukocytes and microglia, of CNV mice: vessels of the spontaneous CNV were mostly negative for TLR2 staining, although some cells that tightly associated with the CNV vessels, likely leukocytes and/or microglia, were positive for TLR2. Feng teaches (same §) their results suggest that the primary source of TLR2 in the eye is the RPE [emphasis added]. Altogether, the teachings of Feng would have made it obvious to deliver the TLR2 antagonist to the site of TLR2 protein, which Feng teaches is the RPE, retinal microglia, and peripheral blood mononuclear cells. An artisan knows that a leukocyte is a kind of mononuclear phagocyte because Encyclopedia teaches that is the case.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify Feng’s method of treating CNV/AMD by administering a neutralizing anti-TLR2 antibody via intravitreal injection with Feng’s teachings about the location of TLR2 protein for the benefit of administering the neutralizing anti-TLR2 antibody to the exact location of the TLR2 protein and achieving the best inhibition. One would have been motivated to do so with a reasonable expectation of success because Feng teaches that (§Introduction ¶4) the TLR2 pathway is a therapeutic target to prevent blindness in patients with AMD, that (Fig. 5) the neutralizing anti-TLR2 antibody suppressed the growth of CNV vessels, and they observed TLR2 expression in retinal microglia and leukocytes (which are a kind of mononuclear phagocyte), and an artisan would have wanted to directly administer the treatment to the site of injury. Therefore the limitations of Claim 17 would have been obvious in view of the teachings of Feng.
Feng teaches a method of treating AMD comprising administering the step of decreasing TLR2 activation by administering a neutralizing anti-TLR2 antibody. Feng also teaches (§Main text ¶2-3) CEP is a product of lipid oxidation and is an activating ligand for TLR2. Feng teaches (same §) microenvironments with high oxidative stress, including the neural retina, promotes lipid oxidation and formation of CEP which could result in chronic TLR2 activation and inflammation. Those are general teachings about the role of CEP in the eye causing inflammation and chronic TLR2 activation.
Feng does not teach the method of treating AMD wherein the AMD is dry AMD (i.e., Claim 4). Note that the instant claims recite only that the method comprises the step of administering a pharmaceutically effective amount of a TLR2 antagonist to decrease the expression or activation of TLR2; the language of the claims (“compris[ing] the step…”) is open and therefore allows for other components to be administered.
Doyle teaches using anti-TLR2 treatment to treat dry AMD and using a Mal peptide inhibitor. Doyle is drawn to TLR2’s role in bridging oxidative damage and that TLR2 is a therapeutic target for AMD. Doyle teaches (§Purpose) deposition of complement component 3 (C3) subjacent to RPE and increased oxidative protein modifications are pathological hallmarks of disease. Dysregulated activation of the alternative complement cascade is involved in AMD progression. Doyle teaches (§Results) CEP is a biomarker of AMD and a ligand for TLR2 that induces secretion of C3. Doyle teaches that CEP promotes formation of membrane attack complex (MAC) formation and induction of MCP-1 chemokine, correlating with increased TLR2+ cells observed in the choriocapillaris of AMD donor eyes. Doyle teaches (same §) an anti-TLR2 neutralizing antibody and a Mal peptide inhibitor inhibited MAC formation:
MAC formation was inhibited using an anti-TLR2 neutralising antibody and a Mal peptide inhibitor. We show that C3 deposition, RPE atrophy and photoreceptor cell death are ameliorated by TLR2 blockade in oxidative stress models of retinal degeneration that mimic aspects of AMD and directly implicate TLR2 as a bridge between oxidative damage and complement-mediated pathology.
Doyle concludes that these findings indicate anti-TLR2 treatment has therapeutic utility for the pathology associated with dry AMD [emphasis added].
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating wet AMD comprising administering the step of decreasing TLR2 activation by administering a neutralizing anti-TLR2 antibody of Fang with the teachings and Mal peptide inhibitor of Doyle for the benefit of preventing MAC formation and treating dry AMD. One would have been motivated to do so with a reasonable expectation of success because the combined teachings of Feng and Doyle implicate CEP in inflammation that induces TLR2 activation that can lead to either wet AMD and/or dry AMD and because Doyle teaches that an anti-TLR2 neutralizing antibody and a Mal peptide inhibitor inhibited MAC formation and suggested using anti-TLR2 therapy to treat dry AMD. Modifying the method of treating AMD comprising administering the step of decreasing TLR2 activation by administering a neutralizing anti-TLR2 antibody with the suggestion to use anti-TLR2 to treat dry AMD and the Mal peptide inhibitor would have produced a method with the limitations of Claim 4.
Claim(s) 1 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Feng as applied to Claim 1 above, and further in view of Dasu (et al. 2009. Candesartan inhibits Toll-like receptor expression and activity both in vitro and in vivo. Atherosclerosis 202:76-83, “Dasu”) and US Patent Application Publication No. US 2007/0203211 (published on 30 August 2007, “App211”), as evidenced by Lowe (2016. Parenteral drug delivery. Basicmedical Key. Available online at basicmedicalkey.com/parenteral-drug-delivery/. Accessed on 28 October 2025, “Lowe”) and Bourges (et al. 2003. Ocular Drug Delivery Targeting the Retina and Retinal Pigment Epithelium Using Polylactide Nanoparticles. IOVS 44[8]:3562-3569, “Bourges”). This rejection is necessitated by the claim amendments.
The teachings of Feng as applicable to Claim(s) 1 have been described above.
Feng teaches a method of treating AMD comprising administering the step of decreasing TLR2 activation by administering a neutralizing anti-TLR2 antibody.
Feng does not teach the method of treating AMD, wherein the TLR2 antagonist is the small molecule TLR2 antagonist 2-ethoxy-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylic acid (i.e., Claim 20). Note that the Spec. discloses that (¶30) that compound is also called candesartan cilexetil or Atacand®.
However, Dasu teaches (§Abstract-Conclusion) TLR2 expression at both mRNA and protein levels was inhibited by candesartan both in vitro and in vivo. Dasu teaches (§1. Introduction ¶2) candesartan is a known and “widely used” angiotensin II type 1 receptor blocker and anti-atherosclerotic medication.
App211 (§Abstract) is drawn to methods for the prevention or treatment of intraocular angiogenic diseases such as age-related macular degeneration. App211 teaches (¶20) compounds that can be administered to treat AMD include candesartan cilexetil as well as salts, hydrates, solvates of its free form or salt form or derivatives or prodrugs. App211 teaches (¶21-22) such medicaments may be used to treat intraocular angiogenic diseases including AMD. App211 teaches (§Example 1, starts at ¶28, Table 1) candesartan cilexetil provided significant improvements when tested in mouse eyes. App211 teaches (¶24) administering the antagonists of their invention parenterally.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating AMD by administering a TLR2 antagonist of Feng with the candesartan cilexetil of Dasu and US211 for the benefit of treating AMD with a compound (i.e., candesartan cilexetil) known to inhibit two receptors (angiotensin II receptor and TLR2) whose activations are known to contribute to AMD. One would have been motivated to do so because the combined teachings of Feng, Dasu, and App211 indicate that candesartan antagonizes/inhibits two receptors whose activations contribute to AMD and an artisan would have wanted to try to inhibit both receptors to provide as much relief to a patient as possible. One would have been motivated to do so with a reasonable expectation of success because Feng teaches administering a TLR2 antagonist to treat AMD, App211 teaches administering candesartan cilexetil (and its derivatives) to treat AMD, and Dasu teaches that candesartan (i.e., one such derivative of candesartan cilexetil) is a TLR2 inhibitor (i.e., a TLR2 antagonist). An artisan would have used any TLR2 antagonist to carry out Feng’s method and they would have chosen candesartan because Dasu teaches candesartan decreases TLR2 protein and mRNA expression, because Feng teaches TLR2 activation exacerbates inflammation underlying AMD, and because App211 teaches candesartan treats AMD. Administering candesartan would have decreased TLR2 and antagonized angiotensin II receptor, thereby treating AMD on two fronts.
Evidence provided by Lowe (§Reasons for choosing parenteral administration, entire §; § Ophthalmic injections) and Bourges (§Abstract-Conclusions) indicates that ophthalmic injections are a form of parenteral delivery (which App211 teaches at ¶24) and such injections are commonly used to deliver a drug to the RPE.
Altogether, the method of Claim 20 would have been obvious in view of Feng, Dasu, App211, and the evidence of Lowe and Bourges.
Claim(s) 1 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Feng as applied to Claim 1 above, and further in view of International Patent Application Publication No. WO 2005/028509 (published on 31 March 2005, “WO509”), as evidenced by Lowe (2016. Parenteral drug delivery. Basicmedical Key. Available online at basicmedicalkey.com/parenteral-drug-delivery/. Accessed on 28 October 2025, “Lowe”) and Bourges (et al. 2003. Ocular Drug Delivery Targeting the Retina and Retinal Pigment Epithelium Using Polylactide Nanoparticles. IOVS 44[8]:3562-3569, “Bourges”). This rejection is necessitated by the claim amendments.
NOTE: references to p. # in WO509 refer to the PDF p. #. References to ¶ # count ¶1 as the first full ¶ on the p.
The teachings of Feng as applicable to Claim(s) 1 have been described above.
Feng teaches a method of treating AMD comprising administering the step of decreasing TLR2 activation by administering a neutralizing anti-TLR2 antibody. Feng teaches (§Abstract) TLR2 plays an inflammatory role in AMD and TLR2 induced robust expression of proinflammatory cytokines, and end products of lipid oxidation had a synergistic effect on TLR2 activation. Feng teaches (§Discussion ¶3) enhanced TLR2 activation exacerbates the TLR2-mediated inflammatory response in the RPE and suggests (same §, ¶4-5) inhibiting TLR2 activation could be an efficacious therapeutic strategy for treating CNV or AMD.
Feng does not teach the method of treating AMD, wherein the TLR2 antagonist is the specific anti-TLR2 antibody T2.5.
However, WO509 teaches (p. 2 ¶1) T2.5 is an anti-TLR2 monoclonal Ab that is cross-reactive to both mouse and human TLR2. WO509 teaches (p. 4 ¶3) T2.5 specifically inhibits or blocks mammalian TLR2 by specifically binding the extracellular domains of TLR2. WO509 teaches (same §) inhibiting TLR2 can prevent and/or treat inflammatory processes and/or processes induced by chronic inflammation. WO509 teaches (p. 5 ¶2) T2.5 specifically recognizes both mouse and human TLR2. WO509 teaches (p. 16 ¶5) therapeutic uses for the Ab and teaches they can be administered parenterally. WO509 teaches (p. 21 ¶1, Fig. 6 caption; § Antibody mediated interference with TLR2 specific immune responses towards systemic challenge, starts on p. 26, final ¶) the anti-TLR2 Ab T2.5 inhibits TLR2 activation in mice.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating AMD by administering a TLR2 antagonist of Feng with the specific anti-TLR2 antibody of WO509 for the benefit of treating AMD in humans by using a human-reactive anti-TLR2 Ab that reduces TLR2 activation-induced inflammation (specifically WO509’s T2.5 anti-TLR2 antibody) in Feng’s method. One would have been motivated to do so with a reasonable expectation of success because WO509 teaches (p. 2 ¶1) using the T2.5 anti-TLR2 Ab to prevent and/or treat inflammatory processes or any process induced by chronic inflammation and because Feng teaches (§Introduction, §Discussion) TLR2 activation underlies inflammation that leads to development of AMD and because Feng suggests inhibiting TLR2 activation to treat AMD.
Evidence provided by Lowe (§Reasons for choosing parenteral administration, entire §; § Ophthalmic injections) and Bourges (§Abstract-Conclusions) indicates that ophthalmic injections are a form of parenteral delivery (which WO509 teaches at p. 16 ¶5) and such injections are commonly used to deliver a drug to the RPE.
Altogether, the method of Claim 22 would have been obvious in view of Feng, WO509, and the evidence of Lowe and Bourges.
Response to Arguments
Applicant's arguments filed 10 September 2025 have been fully considered but they are not persuasive. Arguments are responded to below. Arguments that are no longer relevant are not addressed.
112(a) written description
The written description rejection of the claims is maintained because Applicant has not demonstrated possession of any species of any TLR2 antagonist or any decreaser of TLR2 expression. Applicant has not demonstrated that their method steps would work with any antagonist that decreases TLR2 expression because they have not administered any antagonist that decreases TLR2 expression. Applicant has not demonstrated their method would work with any anti-TLR2 antagonizing Ab or any fragment of any anti-TLR2 antagonizing Ab. The claims recite a genus of compounds identified only by their function (i.e., an antagonist of a TLR [that] decrease[s] the expression or activation of the TLR wherein the TLR is TLR2 and wherein the TLR[2] antagonist is an Ab-like TLR antagonist or an Ab fragment TLR[2] antagonist) but Applicant’s Spec. does not adequately describe the structure necessary for the claimed functions in such a way that an artisan would readily identify what are the members of the genus. That indicates that at time of filing Applicant as not in possession of the full breadth of the claimed invention.
The claims broadly recite administering a pharmaceutically effective amount of any antagonist that decreases expression or activation of TLR2 and the method wherein the antagonist is any anti-TLR2 antagonizing Ab or any fragment of any anti-TLR2 antagonizing Ab. However, Applicant does not show species demonstrating those outcomes in a number commensurate with the breadth of the claims. Furthermore, the claims as written encompass any species of TLR2 antagonists that are decreasers of TLR2 activation or expression, including those that have not yet been invented or discovered. Clearly Applicant cannot be in possession of those species. Yet, those are encompassed by the claims as instantly presented.
Applicant argues against the WD rejections on pp. 7-10. Applicant argues (p. 8, first full ¶) specific antagonists are now recited in the instant claims. Note that the WD rejection does not apply to Claims 20 or 22.
Applicant argues that (p. 9):
there is no per se rule that an adequate written description of an invention that involves a biological macromolecule must contain a recitation of known structure. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics, so long as a person skilled in the art would recognise that the inventor had possession of the claimed invention.
That is not found persuasive because the written description requirement for a genus may be satisfied through sufficient description of a representative number of species by “…disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.” Thus when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. A person of ordinary skill would recognize—and Watson teaches—that Abs are produced by hypermutation and thus are very diverse.
"A sufficient description of a genus… requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618. Note that the Spec. names only two anti-TLR2 Abs. The Spec. doesn’t identify any structure common to TLR2 antagonists and does not describe any requisite structure of an anti-TLR2 Ab fragment.
Applicant argues (p. 9, final ¶) that any TLR2 antagonist can be used in their invention. That is not persuasive because the issue is that an artisan would not necessarily know what is or is not a TLR2 antagonist, an anti-TLR2 antagonist Ab, or a fragment of an anti-TLR2 antagonist Ab that can be used in the invention. The fact that the Spec. discloses (¶33) that OM-174 is a TLR antagonist goes to the point that what is or is not a TLR2 antagonist is inadequately described in the Spec. As discussed in §Election/Restriction and the 112(a) rejection, Yu teaches that OM-174 is a TLR2 agonist.
The statutes require that Applicant had possession of the claimed invention at time of filing. Since it was not possible for Applicant to have been in possession of any species of TLR2 antagonists and decreasers of TLR2 activation or expression, including those that have not yet been invented or discovered, the statutory requirement has not been met.
102 and 103 rejections
Applicant argues the 102 and 103 rejections on pp. 10-14.
Applicant argues that Feng fails to anticipate the claimed invention because:
Claim 1 recites a combination that includes, among other things:
"A method of treating age-related macular degeneration in a subject in need thereof, the method comprising the step of administering a pharmaceutically effective amount of an antagonist of a toll-like receptor to the retinal pigment epithelium of the subject to decrease the expression or activation of the toll-like receptor in the subject and so treat age-related macular degeneration in the subject, wherein the toll-like receptor is TLR2."
At the very least, Feng fails to disclose or suggest any of these exemplary features recited in the independent Claims 1. Feng is not concerned with nor teaches treating dry AMD, non- exudative AMD, or non-neovascular AMD; and actually teaches therapy in combination with anti- VEGF therapy for "wet" AMD.
That is not persuasive because Applicant has not described in their arguments the exemplary features recited in the independent Claims 1. As discussed in the 102 rejection, Feng teaches (§Abstract) choroidal neovascularization (CNV) is a major cause of blindness for AMD patients and inhibiting TLR2 treated CNV: TLR2 antagonism effectively suppressed initiation and growth of spontaneous choroidal neovascularization in a mouse model. Feng teaches (§Introduction ¶4) their studies indicate dysregulated TLR2 activation functions in CNV pathogenesis and these studies point to the TLR2 pathway as a potential therapeutic target to prevent blindness in patients with AMD. Claim 1 recites simply a method of treating age-related AMD in a subject in need thereof, the method comprising the step of administering a pharmaceutically effective amount of an antagonist of TLR2 to the retinal pigment epithelium of the subject to decrease expression or activation of the TLR2 in the subject and so treat age-related AMD in the subject. Nothing about that claim requires that the AMD be dry AMD. Since Feng teaches antagonizing TLR2 to suppress CNV and teaches this pathway as a therapeutic target for preven