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, 6-10, 17 and 20-23 are pending. Claims 6-10 and 23 are withdrawn from consideration as being drawn to a nonelected invention.
Status of the Application
Applicant’s response and amendment filed 30 April 2026 are acknowledged and entered.
Applicant has amended Claim 1 and cancelled Claim 4.
Response to Amendment
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amended Claim 1 to overcome the 112(a) written description rejection; the 112(a) written description rejection is not withdrawn.
The 102 rejection over Feng is withdrawn.
The 103 rejections are maintained and updated.
Claims 1, 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Rejections not reiterated here are withdrawn.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 Objections
Claim 17 is objected to for minor informalities.
Claim 17 recites: The method of claim 1, wherein the method comprises administering a pharmaceutically effective amount of an antagonist of a toll-like receptor to the subject to decrease the expression or activation of the toll-like receptor, wherein the method further comprises administering the toll-like receptor antagonist to the retinal pigment epithelium, and wherein the method further comprises administering the toll-like receptor antagonist to cells selected from the group consisting of retinal microglia cells, muller glia cells and mononuclear phagocyte but should take out the underlined part because that is redundant with Claim 1 because it recites …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….
Therefore Claim 17 should recite: The method of claim 1, wherein the method further comprises administering the toll-like receptor antagonist to cells selected from the group consisting of retinal microglia cells, muller glia cells and mononuclear phagocyte.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 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, 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 and wherein the AMD is dry AMD, nonexudative AMD, or non-neovascular AMD (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”, of record) 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 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 § 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.
Claim(s) 1 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over 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) and Hageman (et al. 2008. Age-Related Macular Degeneration [AMD]. In: Kolb H, Fernandez E, Jones B, et al., eds. Webvision: The Organization of the Retina and Visual System [Internet]. Salt Lake City, UT: University of Utah Health Sciences Center, “Hageman”). This rejection is new in response to the claim amendments.
Doyle teaches using anti-TLR2 treatment to treat dry AMD. Doyle is drawn to TLR2’s role in bridging oxidative damage, complement pathology, and AMD. Doyle teaches TLR2 is a therapeutic target for dry AMD.
Doyle teaches (§Purpose) deposition of complement component 3 (C3) subjacent to RPE and increased oxidative protein modifications are pathological hallmarks of disease [i.e., AMD]. 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 C3 secretion. 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 [Ab] 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].
Doyle teaches the anti-TLR2 neutralizing Ab ameliorated RPE atrophy, their findings directly implicate TLR2 as a bridge between oxidative damage and complement-mediated pathology, and suggests using anti-TLR2 treatment to treat dry AMD.
Doyle does not explicitly teach administering the anti-TLR2 neutralizing Ab to the RPE.
However, Hageman, drawn to a review about AMD, teaches (§Clinical Aspects of AMD-Clinical Presentation of AMD ¶1-3) dry AMD is characterized by drusen along the RPE and (Fig. 3) RPE disruption is present in early dry AMD.
Regarding pharmaceutical compositions, Hageman teaches (§Conclusion ¶3) development of pharmacological approaches for treating AMD and (Fig. 36) injecting Ab treatment to the eye for other forms of AMD.
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 Doyle’s method of treating dry AMD comprising inducing a TLR2 blockade by administering a neutralizing anti-TLR2 antibody with Hageman’s teachings about cells affected in early dry AMD, namely cells of the RPE. That would have led the artisan to administer the anti-TLR2 neutralizing Ab to the RPE of a subject afflicted with dry AMD. They would have done so for the benefit of administering the treatment to the tissue primarily affected in dry AMD, which Hageman indicates is the RPE. One would have been motivated to do so with a reasonable expectation of success because Doyle teaches anti-TLR2 treatment has therapeutic utility for pathology associated with dry AMD and teaches (§Methods) they used mouse models to determine the relationship between the innate immune system and retinal degeneration and successfully used TLR2 blockade to ameliorate RPE atrophy and photoreceptor cell death. One would have been motivated to do so with a reasonable expectation of success because Doyle teaches (§Results) TLR2 blockade ameliorated RPE atrophy.
Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). The motivation to combine falls under an “obvious to try” rationale; see MPEP 2143(I)(E):
To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.
Regarding (1): Doyle teaches (§Purpose) AMD is the primary cause of vision loss in the developed world. Hageman teaches (Fig. 3) dry AMD causes RPE disruption. That indicates treating dry AMD was a recognized problem.
Regarding (2): Doyle teaches (§Conclusions) anti-TLR2 treatment has therapeutic utility for treating dry AMD. That indicates there was but a single identified, predictable potential solution to the recognized need of treating dry AMD: administering an anti-TLR2 treatment.
Regarding (3): a person of ordinary skill in the art could have pursued the known potential solution with a reasonable expectation of success because Doyle demonstrated some success in ameliorating AMD pathology and because Doyle suggests using their method to treat dry AMD.
The pharmaceutical composition comprising the Ab would have been obvious because a person of ordinary skill understands drugs have to be administered and Hageman teaches it was routine and conventional to administer pharmaceutical compositions comprising Ab therapies.
Modifying Doyle’s method of treating dry AMD comprising the step of administering TLR2 blockade via an anti-TLR2 neutralizing antibody with Hageman’s teachings about the RPE being a location affected in early AMD would have produced a method with the limitations of Claims 1 and 21.
Claim(s) 1, 17, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Doyle and Hageman as applied to Claims 1 and 21 above, and further in view of Ambati (et al. 2014. Immunology of age-related macular Degeneration. Nat. Rev. Immunol. 13:438, “Ambati”) and evidence of Hume (2006. The mononuclear phagocyte system. Curr. Opin. Immunol. 18[1]:49-53 ABSTRACT ONLY, “Hume”). This rejection is necessitated by the claim amendments.
The teachings of Doyle and Hageman as applicable to Claim(s) 1 and 21 have been described above.
Doyle and Hageman make obvious a method of treating dry AMD comprising the step of administering a pharmaceutical composition comprising an anti-TLR2 treatment to the RPE of a subject. Doyle’s teachings indicate that treatment would decrease activation of TLR2 and so treat AMD in the subject.
Doyle and Hageman do not explicitly teach administering the pharmaceutical composition to retinal microglial cells or to mononuclear phagocytes.
However, Ambati teaches retinal microglial cells are affected in dry AMD. Ambati teaches (§Box 1) the RPE is where drusen deposits accumulate and the RPE is a major source of drusen which comprise (same § ¶2-3) inflammation markers including proteins with CEP modifications and C3.
Ambati teaches (Fig. 1, §Immune surveillance in maintaining retinal health ¶1-3) the resident inflammatory cells of the retina are the microglia and that their migration is necessary to eliminate visual byproducts and maintain vision. Ambati teaches (same §; Fig. 1c) inflammatory signals in the retinal evoke innate immune responses and, in AMD, retinal microglia and macrophages accumulate in the subretinal space. Ambati teaches (same §) recruited macrophages modulate disease. Ambati teaches (§Dysregulated immune activation in AMD ¶1) innate immune activation induces/advances AMD pathology and contributes to vision loss in AMD. Ambati teaches (§Dysregulated immune activation in AMD-Inflammasome activation ¶2) CEP activates the inflammasome in macrophages.
Altogether, Ambati shows (Fig. 1c) microglial cells (i.e., the resident inflammatory cells of the retina) accumulate in the RPE in AMD. Ambati teaches microglia and macrophages contribute to inflammation, and inflammation contributes to AMD pathology. The following excerpt of Ambati’s Fig. 1 shows microglial accumulation in the RPE and macrophage infiltration of the eye occurs in dry AMD:
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As discussed above, Doyle teaches CEP is a biomarker for AMD and a ligand for TLR2 activation that induces C3 secretion. Doyle indicates TLR2 activation induces MAC formation and inflammation but TLR2 blockade ameliorates C3 deposition (i.e., a form of inflammation), RPE atrophy, and photoreceptor cell death.
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 Doyle and Hageman’s method of treating dry AMD by administering an anti-TLR2 treatment to the RPE (which would decrease activation of TLR2) with Ambati’s teachings about the role of retinal microglia and macrophages in inflammation and the role of inflammation in AMD. That would have motivated the artisan to administer the TLR2 inhibiting treatment to the retinal microglia and macrophages in the RPE. One would have done so for the benefits of administering the anti-TLR2 treatment to inflammatory retinal microglia and macrophages within the RPE and thereby (1) inhibiting TLR2 in inflammatory cells that contribute to AMD, (2) downregulating inflammation, and (3) treating dry AMD. One would have been motivated to do so with a reasonable expectation of success because both Ambati and Doyle teach or indicate that inflammation plays a role in dry AMD, and the artisan would have wanted to inhibit inflammation in cells in the RPE—resident cells and immune cells that have infiltrated the RPE. Inhibiting TLR2 in retinal microglia and macrophages would have eliminated a source of inflammation and reduced the amount of inflammation in the eye, thereby treating dry AMD.
Using Doyle and Hageman’s method of treating dry AMD by carrying out the step of administering to a subject a pharmaceutical composition comprising an anti-TLR2 treatment to the RPE (which would decrease activation of TLR2 and so treat AMD in the subject) and administering the method to Ambati’s retinal microglia and macrophages would have produced the method of Claim 17.
Note that although Ambati doesn’t use the term “mononuclear phagocyte” which is recited in the claims, Hume teaches (§Abstract) macrophages are a species within the genus of mononuclear phagocytes.
Claim(s) 1 and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Doyle and Hageman as applied to Claims 1 and 21 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”, of record) and US Patent Application Publication No. US 2007/0203211 (published on 30 August 2007, “App211”, of record). This rejection is updated in response to the claim amendments.
The teachings of Doyle and Hageman as applicable to Claim(s) 1 and 21 have been described above.
Doyle and Hageman make obvious a method of treating dry AMD comprising the step of administering a pharmaceutical composition comprising an anti-TLR2 treatment to the RPE of a subject. Doyle’s teachings indicate that treatment would decrease activation of TLR2 and so treat AMD in the subject.
Doyle 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 an anti-TLR2 treatment of Doyle and Hageman 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 Doyle teaches a TLR2 blockade to treat dry AMD and the combined teachings of 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 Doyle teaches anti-TLR2 treatment to treat dry 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 Doyle’s method and they would have chosen candesartan because Dasu teaches candesartan decreases TLR2 protein and mRNA expression, because Doyle teaches (§Results, §Conclusions) TLR2 blockade ameliorates RPE atrophy and photoreceptor cell death in dry AMD and states anti-TLR2 treatment has therapeutic utility for pathology associated with 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. Although App211 teaches candesartan can be used for angiogenic diseases, it would have been obvious in view of Doyle to use it as a TLR2 inhibitor to treat dry AMD.
Altogether, the method of Claim 20 would have been obvious in view of Doyle, Hageman, Dasu, and App211.
Claim(s) 1 and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Doyle and Hageman as applied to Claims 1 and 21 above, and further in view of International Patent Application Publication No. WO 2005/028509 (published on 31 March 2005, “WO509”, of record). This rejection is updated in response to 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 Doyle and Hageman as applicable to Claim(s) 1 have been described above.
Doyle and Hageman make obvious a method of treating dry AMD comprising the step of administering a pharmaceutical composition comprising an anti-TLR2 treatment to the RPE of a subject. Doyle’s teachings indicate that treatment would decrease activation of TLR2 and so treat AMD in the subject.
Doyle 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 (§Abstract) a pharmaceutical composition comprising the Ab. 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 dry AMD by administering an anti-TLR2 treatment of Doyle and Hageman 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 the method of Doyle and Hageman. 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 Doyle teaches (§Results, §Conclusions) TLR2 blockade ameliorates RPE atrophy and photoreceptor cell death in dry AMD and states anti-TLR2 treatment has therapeutic utility for pathology associated with AMD.
Altogether, the method of Claim 22 would have been obvious in view of Doyle, Hageman, and WO509.
Response to Arguments
Applicant's arguments filed 30 April 2026 have been fully considered but they are not persuasive. Arguments are responded to below. Arguments that are no longer relevant are not addressed.
Claim objection
Claim 17 is objected to for redundant phrasing.
112(a) written description (WD)
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 activation/expression. Applicant has not disclosed what is the structure of a TLR2 antagonist or decreaser of TLR2 activation/expression that can be used in their methods. 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, but the Spec. discloses no structure(s) responsible for the function of decreasing TLR2 expression or activation.
Applicant argues against the WD rejections on pp. 6-8. Applicant argues (p. 6 §C ¶3) their example showing that TLR2 KO protects the retina from oxidative damage is sufficient to provide written description support. That is not found persuasive because the WD rejection is not an enablement rejection. The WD is about possession:
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…
There are several points at which possession isn’t supported:
The claims recite and encompass an antagonist of TLR2 that decreases expression or activation of TLR2. But Applicant hasn’t stated what are the structural characteristics of those antagonists of TLR2 that decrease expression or decrease activation of TLR.
Furthermore, the Claims recite Ab TLR2 antagonists and Ab fragment TLR2 antagonists. Again, Applicant’s Spec. hasn’t disclosed what structure of an Ab TLR2 antagonist or Ab fragment TLR2 antagonist is necessary to produce the outcome of antagonizing TLR2. As discussed in the WD rejection, Abs are incredibly diverse because Ab production involves hypermutation. In view of that hypermutation, there is no evidence that any anti-TLR2 Ab will perform as claimed to antagonize any TLR2.
Applicant argues (§C ¶4) their examples demonstrate efficacy of their method. That is not persuasive that the claims don’t have a WD problem because Applicant hasn’t demonstrated possession of a representative number of decreasers of TLR2 expression or activation to claim the entire genus. They haven’t demonstrated possession of a representative number of TLR2-antagonizing Abs or TLR2-antagonizing Ab fragments to claim the entire genus of any Ab or Ab fragments. Nothing in the Spec. discloses what constitutes a suitable fragment of a TLR2-antagonizing Ab.
Applicant then argues (§C ¶6) that any TLR2 antagonist can be used in their invention. That is not persuasive to overcome the WD problem 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.
Applicant argues that (§C ¶5):
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 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.
The statutes require that Applicant had possession of the claimed invention at time of filing. Since Applicant hasn’t disclosed any correlation between function of decreasing expression/activation of TLR2 and structure of a TLR2 antagonist, a TLR2 antagonist Ab, or a fragment of a TLR2 antagonist Ab, the statutory requirement has not been met.
103 rejections
Applicant argues the 103 rejections on pp. 8-9. The 102 rejection is withdrawn in view of the claim amendments but the 103 rejections are maintained but updated as necessitated by the claim amendments.
Applicant argues that (§D ¶2-6) Feng discusses a different kind of AMD—wet AMD—and that is pathologically separate from the dry AMD claimed.
Those arguments are not relevant because Doyle is now relied upon as the primary reference.
Applicant argues that (§D ¶5-6) Doyle does not teach treating dry AMD by administering an antagonist that decreases activation of TLR2 in the manner recited in pending Claims 1, 17, and 21. Since Doyle very clearly teaches administering an anti-TLR2 treatment for dry AMD (i.e., Conclusions: These findings indicate anti-TLR2 treatment has therapeutic utility for the pathology associated with dry AMD), Applicant’s statement in the manner recited in pending Claims 1, 17, and 21 is interpreted to mean the recitation about administering the treatment to the RPE or cell types recited in Claim 17.
Those arguments aren’t found persuasive because Hageman teaches (Fig. 3; § Clinical Aspects of AMD-Clinical Presentation of AMD ¶1) the RPE atrophies in early dry AMD and teaches (§Conclusion ¶3) development of pharmacological approaches for treating AMD and (Fig. 36) injecting Ab treatment to the eye for other forms of AMD. That indicates it was routine and conventional to administer treatments, including Ab treatments, to the eye. Then, it would have been for an artisan to administer the anti-TLR2 neutralizing Ab treatment of Doyle to the cells that Hageman teaches are afflicted in dry AMD. The, Ambati teaches inflammation plays a role in AMD and teaches retinal microglial cells and macrophages contribute to inflammation that contributes to AMD. A desire to reduce inflammation in the RPE would have motivated an artisan to administer the anti-TLR2 treatment of Doyle and Hageman to the other cell types that contribute to inflammation.
Therefore the 103 rejections are maintained.
Conclusion
Claims 1, 17, and 20-22 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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RUTHIE S ARIETI
Examiner
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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