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 .
Claim Status
Claims 1-2, 15, 17, 39, 48, 55, and 60-78 are pending. In the Reply filed 4/29/2026, claims 9, 14, 49-54, and 56-58 were canceled; claims 1-2, 15, 17, 39, 48, and 55 were amended; claims 61-78 were newly added; and claims 2, 15, 48, and 63-78 are withdrawn. Claims 1, 17, 39, 55, and 60-62 are presently considered.
Election/Restrictions
Applicant’s election of Group I (methods) and the species corresponding to Example 7 in the reply filed on 10/13/2025 was previously acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Example 7 pertains to a combination therapy of AIBP, APOA-I, and Anti-VEGF Antibody, for the treatment of Choroidal neovascularization1 (CNV) (see Spec. filed 11/18/2022 at ¶[0125]). The originally elected species is understood to be the treatment of a laser-induced CNV mouse model with AIBP, apoA-1, and an anti-VEGF antibody (see Spec. filed 11/18/2022 at ¶¶[0134]-[0135], Figures 15E and 21; see Reply filed 10/13/2025 at 9), via intravitreal injection2. The mouse model is an admitted obvious variant for humans, and therefore the elected species is understood to include both CNV mouse models and human individuals (see Reply filed 10/13/2025 at 8-9). The compounds utilized within the originally elected species of method are understood as follows: ApoA-1 is SEQ ID NO: 33; AIBP is understood to be SEQ ID NO: 14; and the Anti-VEGF agent is understood to be the Anti-VEGF antibody of “AF-493-NA”5.
The Applicant did not identify what claims read upon the originally elected species (see, e.g., Requirement mailed 7/02/2025 at 6 at 2nd full ¶, noting that the “reply must also identify the claims readable on the elected species, including any claims subsequently added”). However, amended claim 2 now requires a patient limitation not satisfied by Example 7; amended claim 17(d) was canceled and claim 17 now requires an antibody other than AF-493-NA as present in the originally elected species; amended claim 48 no longer reads upon “before, during, or after” (i.e., at all times), but instead only reads upon “before or after”, but Example 7 does not specify, and therefore amended claim 48 does not read upon the originally elected species; amended claim 55 now requires an anti-VEGF antibody other than AF-493-NA as present in the originally elected species; furthermore, newly added claims 63, 65, 67, 69, 71, 73, 75, and 77 (and their dependents, claims 64, 66, 68, 70, 72, 74, 76, and 78) do not recite nor require the anti-VEGF antibody of AF-493-NA as present in the originally elected species. Accordingly, claims 2, 15, 17, 55, and 63-78 do not read upon the originally elected species. Regarding instant claims 1, 39, and 60-62, in the Reply filed 4/29/2026, claims 1 and 39 were amended to recite and require a patient population limitation, namely “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”, which excludes the originally elected species of Example 7 because such subjects were not “previously treated” with a separate treatment and deemed “nonresponsive” to such treatment6. Accordingly, no pending claims are directed to the originally elected species following the amendments filed 4/29/2026.
Per MPEP § 803.02(III)(A),
Should applicant, in response to a rejection of a Markush claim, overcome the rejection by amending the Markush claim to exclude the species anticipated or rendered obvious by the prior art, the amended Markush claim will be examined again. The examination will be extended to the extent necessary to determine patentability of the Markush claim. In the event prior art is found during this examination that anticipates or renders obvious the amended Markush claim, the claim will be rejected and the action can be made final unless the examiner introduces a new ground of rejection that is neither necessitated by applicant’s amendment of the claims nor based on information submitted in an information disclosure statement filed during the period set forth in 37 CFR 1.97(c) with the fee set forth in 37 CFR 1.17(p).
Accordingly, examination has been extended to a non-elected species of treatment of CNV in a patient following anti-VEGF-Therapy failure, by intravitreal administration of a combination therapy comprising Anti-VEGF antibody of ranibizumab, instant SEQ ID NO: 1 (i.e., AIBP), and instant SEQ ID NO: 3 (i.e., ApoA-I). The non-elected species is understood to read upon instant claims 1, 17, 39, 55, and 60-62; accordingly, claims 17 and 55 are presently rejoined and considered to the extent that these claims read upon a non-elected species that comprises ranibizumab.
Following extensive search and examination, the non-elected species has been deemed anticipated and/or obvious in view of the prior art as applied below. Per MPEP § 803.02(III)(A), this action is final and claims 1, 17, 39, 55, and 60-62 are presently considered.
Claims 2, 15, 48, and 63-78 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/13/2025.
Claims 1, 17, 39, 55, and 60-62 are presently considered.
Information Disclosure Statement
The IDS filed 04/29/2026 is acknowledged and presently considered.
Examiner notes that the fee set forth in 37 CFR 1.17(p) was submitted with the IDS. The Examiner previously noted the existence of art known to the Applicant or Inventor that was not placed in an IDS (see, e.g., Action mailed 12/31/2025 at 5 at final ¶).
Examiner notes that the Declaration identifies that a Co-Inventor provided relevant presentations or seminars (see, e.g., Dec. filed 4/29/2026 at 7 referring to a 2021 lecture entitled “Combination of apolipoprotein-A-T/apolipoprotein-A-T binding protein and anti-VEGF treatment overcomes anti-VEGF resistance in choroidal neovasculaiization in mice. Fu Y. Novel Ophthalmology 2021 - 2nd Global Ophthalmology and Eye Diseases Summit (virtual conference). Vancouver, Canada. November 9-10”; at 8 referring to a 2022 lecture entitled “Combating drug resistance in age-related macular degeneration. Fu, Y. Boston Children's Hospital/Harvard Medical School, Boston. Online presentation. March 28.”). Accordingly, such disclosures were known to the inventors at the time of filing, but have not been placed on record in an IDS at this time.
As stated in the previous action, Applicant is advised that any posters, presentations, ect., presented at any conference regarding CNV, AMD, ApoA-I, AIBP, and/or any anti-VEGF agents are relevant and material to a determination of patentability, and should be placed on record in an IDS (see, e.g., MPEP § 2001, 37 C.F.R. 1.56).
Specification
The sequence listing filed 4/29/2026 is acknowledged.
Drawings
The amendments filed 4/29/2026 to the Specification, removing references to color in the drawings is acknowledged.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Amended claims 1 and 39 are representative of the pending claim scope. In the Response filed 4/29/2026, the claim scope was amended to require intravitreal administration, and to include the “wherein” clause “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”. The applicable claim interpretation is discussed below.
Patient Population: An “individual” is understood to include at least humans and mice (see Spec. filed 11/18/2022 at ¶¶[0134]-[0135]). The amended preamble and newly added “wherein” clause is interpreted in view of MPEP § 2111.02 and MPEP § 2111.04(I), and although the preamble does not recite “in a patient in need thereof” or equivalent language, the newly added “wherein” clause limits the patient population. Specifically, in view of the phrase “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”, the applicable patient population is understood to be limited specifically to patients that have been “previously treated” (for an unspecified amount of time) “with an anti-VEGF therapy” (wherein the specific “anti-VEGF therapy” is not defined or identified), and that were deemed “nonresponsive to said prior anti-VEGF therapy”, wherein the metes and bounds of what is deemed “nonresponsive” is not identified. Accordingly, the patient population is understood to at least require patients to have a condition wherein anti-VEGF therapy was required or prescribed at some point in the past.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
“Treating” is not specifically defined, but is reasonably understood to include all types of treatment, including prophylactic treatment (see, e.g., Spec. filed 11/18/2022 at ¶¶[0008]-[0009], [0011]).
ApoA-I is a protein consisting of SEQ ID NO: 3 (see Spec. filed 11/18/2022 at ¶[0064]), wherein SEQ ID NO: 3 is disclosed as
MKAAVLTLAVLFLTGSQARHFWQQDEPPQSPWDRVKDLATVYVDVLKDSGRDYVSQFEGSALGKQLNLKLLDNWDSVTSTFSKLREQLGPVTQEFWDNLEKETEGLRQEMSKDLEEVKAKVQPYLDDFQKKWQEEMELYRQKVEPLRAELQEGARQKLHELQEKLSPLGEEMRDRARAHVDALRTHLAPYSDELRQRLAARLEALKENGGARLAEYHAKATEHLSTLSEKAKPALEDLRQGLLPVLESFKVSFLSALEEYTKKLNTQ
(see Spec. filed 11/18/2022 at ¶[0064])
“ApoA-I binding protein” (“AIBP”) is understood to be a secreted protein, and is also known in the art as also known as apolipoprotein A-I binding protein, AI-BP, apoA-I binding protein, NAD(P)H-hydrate epimerase, NAXE, NAD(P)HX epimerase, PEBEL, YJEFNl, and APOA1BP (see Spec. filed 11/18/2022 at ¶¶[0050]-[0055]). AIBP is understood to be SEQ ID NO: 1 (see Spec. filed 11/18/2022 at ¶[0081]). However, SEQ ID NO: 1 is referred to as AJ315849.17 (see id.), but the sequence provided at [0081] actually corresponds to NP_658985.28:
MSRLRALLGLGLLVAGSRVPRIKSQTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLSCATAIA KAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ
(see Spec. filed 11/18/2022 at ¶[0081]). The sequences of AJ315849.1 and NP_658985.2 differ because the amino acid bolded above is leucine rather than valine in AJ315849.1. Both sequences are known in the prior art, share 287/288 amino acid resides (>99.6% identity), and both are understood to be an art-recognized human AIBP within the scope of the instant claims (see, e.g., AJ315849 at § “Keywords”; see, e.g., NP_658985.2 at 4 at § “Protein”, referring to it as “apoA-I binding protein”, 3-4 at § Comment). For purposes of applying prior art, the sequence set forth and identified explicitly as “SEQ ID NO: 1” is understood to be the sequence of the AIBP protein (i.e., NP_658985.2).
Amended claim 1(a)(2) and 39(a)(2) now recites “a variant thereof that comprises 175 or more contiguous amino acids of SEQ ID NO: 1 and the ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization”, and this functional limitation does not literally, inherently, or implicitly appear on record. Notably, 175 contiguous amino acids of SEQ ID NO: 1 (a 288-mer) would ostensibly include at least the 175-mer corresponding to positions 1-175, as well as the 175-mer corresponding to positions 113-288 of SEQ ID NO: 1. This is pertinent because such 175-mers only share the common structure of positions 113-175 are responsible for functionality. Positions 113-175 (63-mer) are:
VICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMT
Zero disclosure on record identifies that this minimum shared 63-mer is either necessary or sufficient to convey “the ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization” as presently claimed. Accordingly, such amendments have necessitated issues of written description in view of functional limitations in the absence of a corresponding structure/function relationship of record.
Amended claims 1(b)(2) and 39(b)(2) now recites “a variant thereof that has 150 or more contiguous amino acids of SEQ ID NO: 3 and the ability to bind AIBP”, and this functional limitation does not literally, inherently, or implicitly appear on record. Notably, 150 contiguous amino acids of SEQ ID NO: 3 (a 267-mer) would ostensibly include at least the 150-mer corresponding to positions 1-150, as well as the 150-mer corresponding to positions 117-267 of SEQ ID NO: 3. This is pertinent because such 150-mers are only required to share the common structure of positions 117-150 (i.e., a 34-mer). Positions 117-150 of SEQ ID NO: 3 are as follows:
VKAKVQPYLDDFQKKWQEEMELYRQKVEPLRAEL
Zero disclosure on record identifies that this minimum shared 34-mer is either necessary or sufficient to convey “the ability to bind AIBP” as required by the amended claims. Accordingly, such amendments have necessitated issues of written description in view of functional limitations in the absence of a corresponding structure/function relationship of record.
The term “Anti-VEGF agent” (interpretation set forth in previous action) has been replaced with a requirement for an “anti-VEGF antibody” at claim 1(c), which is understood to include at antibodies against VEGF such as brolucizumab, pegaptanib (MacugenTM), bevacizumab (Avastin™), conbercept (Lumitin™), ranibizumab (Avastin® and LucentisTM) (see Spec. filed 11/18/2022 at ¶[0061]). The “Anti-VEGF agent” and “anti-VEGF antibody” of AF-493-NA used in the originally elected species (see, e.g., Spec. filed 11/18/2022 at ¶[0133]) is not provided with a sequence, but is understood to be a mouse antibody (see search notes).
“Therapeutically effective amount” is understood in view of the description and is understood to include the range of “about 1 mg/kg” to “about 100 mg/kg” of body weight for AIBP, (see Spec. filed 11/18/2022 at ¶[0095]), 0.6-4.8µg of AIBP with a ratio of AIBP to ApoA-I of 1:4.2 (see Spec. filed 11/18/2022 at ¶[0133]) and 5 ng to 5 mg of anti-VEGF antibody (see Spec. filed 11/18/2022 at ¶¶[0135], [0141]). In the absence of explicitly required amounts, any prior art disclosure disclosing successful or therapeutic results are understood to necessarily and inherently involve a therapeutically effective amount as required by the claims.
Additional claim interpretations are provided below.
Denial of Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, US Provisional Application 63/030421 (filed 5/27/2020), and PCT/IB2021/055463 (filed 6/21/2021) each fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Applicable Case Law
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163.
Lack of literal Support
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163.
Amended or new claims 1, 39, and 60-62 lack literal support in either Pro’421 or PCT’493.
The combination of functional limitations and structures at claims 1(a)(2), 1(b)(2), 39(a)(2), and 39(b)(2) do not literally appear on record, wherein the subgenus of structures are defined by both a contiguous minimum length and also by a required functional limitation. This subgenus defined by both a minimum length and a required functional limitation is not literally disclosed in the priority document.
In addition, the “wherein” clause at amended claims 1 and 39 (i.e., “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”), which now limits the patient population, subsequently treated with a triple therapy method including a compound of (a), (b), and (c) (including functionally defined structures at (a)(2) and (b)(2)), wherein “nonresponsive to said prior anti-VEGF therapy” is not clearly defined on record.
Accordingly, claims 1, 39, and their dependents lack literal support in the originally filed disclosure.
Lack of Implicit or Inherent Support
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163. As noted above, the claims are not literally supported by the originally filed disclosure. Accordingly, the relevant issue is whether or not the new amendments and resulting claim scope is implicitly or inherently supported by the originally filed disclosure.
Per MPEP § 2163(I)(B), “[a]n amendment to correct an obvious error does not constitute new matter where the ordinary artisan would not only recognize the existence of the error in the specification, but also recognize the appropriate correction. In re Oda, 443 F.2d 1200, 170 USPQ 268 (CCPA 1971)”. Here, no allegation that the amendments correct an obvious error has been made. Furthermore, upon inspection, Examiner is unable to identify any single “obvious error” that would lead to the instantly amended claim scope. Accordingly, the amendments cannot be said to correct an “obvious error”.
The closest supporting disclosure for the combination of functional limitations and structures of AIBP variants at claims 1(a)(2) and 39(a)(2) appears at paragraphs [0009], and [0076]-[0078] of the provisional, or paragraphs [0079]-[0081] of PCT’463. However, these disclosures do not literally, inherently, or implicitly correspond to the limitations at claims 1(a)(2) and 39(a)(2) because they fail to meaningfully identify what minimal structure is required to achieve the hoped-for and desired “ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization” as presently claimed. Regarding inherent or implicit support, 175 contiguous amino acids of SEQ ID NO: 1 (a 288-mer) would ostensibly include at least the 175-mer corresponding to positions 1-175, as well as the 175-mer corresponding to positions 113-288 of SEQ ID NO: 1. This is pertinent because such 175-mers only share the common structure of positions 113-175 (i.e., 63-mer), which has the structure:
VICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMT
However, zero disclosure on record identifies that this minimum shared 63-mer is either necessary or sufficient to convey “the ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization” as presently claimed and required by claims 1 and 39. To the contrary, the priority documents direct artisans away from this 63-mer, and directs them to utilize numerous other fragments, including 10-mers and sequences sharing only 70% identity with instant SEQ ID NO: 1 (see, e.g., Pro’421 at ¶¶[0076]-[0078]; see also PCT’463 at ¶[0079]-[0081]). At no point do the priority documents direct artisans to a minimal functional sequence required to convey “the ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization” as presently claimed. Rather, the document states that
Function of a polypeptide may be assessed experimentally, for example, by determining activity in an in vitro or in vivo experiment. Whether or not a given polypeptide or polynucleotide is "functional" may be determined by first selecting an appropriate function to assess.
(see, e.g., Pro’421 at ¶[0076] or PCT’463 at ¶[0079]).
Accordingly, the priority document does not literally, implicitly, or inherently teach or disclose the subgenus of structures now claimed, which are defined by both a contiguous length and also by a required functional limitation. Rather, at best, the priority documents discloses a laundry list of structures but fails to specifically identify which structures are sufficient to convey “the ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization” as presently claimed. Instead, the disclosure quoted above, is understood to simply leave the discovery of the metes and bounds of the Applicant’s claimed invention to others to “figure out” in the future, rather than fully describing what exact structures are included or excluded by the claim scope.
The closest supporting disclosure for the combination of functional limitations and structures of ApoA-I variants at claims 1(b)(2) and 39(b)(2) in the provisional (see, e.g., Pro’421 at ¶¶[0033], [0049]-[0116]-[0117], [0129] and Example 7, referring to exogenous, non-variable ApoA-I) differs substantially from the disclosure in PCT’463 (see, e.g., PCT’463 at ¶¶[0063]-[0064]). The provisional document pertains only to full-length, native ApoA-I, and zero guidance regarding any variants of ApoA-I or ranges of contiguous amino acids, or functional limitations defining subgenera of variants appear in the provisional application (see, e.g., Pro’421 at ¶¶[0033], [0049]-[0116]-[0117], [0129] and Example 7). However, PCT’463 contains additional paragraphs missing from the provisional, which generically refer to ApoA-I variants and “functional fragments” having 10, 20, 30, 40, 50, 100, 150, 200, or 250 contiguous amino acids of SEQ ID NO: 3 (see, e.g., PCT’463 at ¶¶[0063]-[0064]). However, this disclosure fails to inherently, implicitly, or literally describe the narrow subgenus recited at instant claims 1(b)(2) and 39(b)(2), because it fails to identify or direct artisans to any functional 150-mer fragments that convey “the ability to bind AIBP” as required by the instant claims. Here, amended claims 1(b)(2) and 39(b)(2) now recites “a variant thereof that has 150 or more contiguous amino acids of SEQ ID NO: 3 and the ability to bind AIBP”, and this functional limitation does not literally, inherently, or implicitly appear on record in any priority document. Notably, 150 contiguous amino acids of SEQ ID NO: 3 (a 267-mer) would ostensibly include at least the 150-mer corresponding to positions 1-150, as well as the 150-mer corresponding to positions 117-267 of SEQ ID NO: 3. This is pertinent because such 150-mers are only required to share the common structure of positions 117-150 (i.e., a 34-mer). Positions 117-150 of SEQ ID NO: 3 are as follows:
VKAKVQPYLDDFQKKWQEEMELYRQKVEPLRAEL
However, zero disclosure on record identifies that this minimum shared 34-mer is either necessary or sufficient to convey “the ability to bind AIBP” as required by the amended claims. Accordingly, there is zero literal, inherent, or implicit support for such claim scope in the priority documents because it is unclear and not described on record which 150-mers do or do not satisfy the functional limitation required at claims 1(b)(2) and 39(b)(2).
Regarding implicit or inherent support for the “wherein” clause at amended claims 1 and 39 (i.e., “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”), the closest supporting disclosure for this clause appears at claims 14, 34, 45, and 49 of the provisional
14 (Provisional and PCT’463). The method of any one of the preceding claims, wherein provision of the AIBP composition reduces resistance to anti-VEGF agents.
34 (Provisional, corresponding to claim 39 in PCT’463). A method of overcoming resistance to an anti-VEGF therapy in an individual, comprising the step of providing to the individual an effective amount of a composition comprising AIBP or a functionally active fragment or derivative thereof.
45 (Provisional, corresponding to claim 50 in PCT’463). The method of any of claims 34-44 [39-49]9, wherein the individual is determined to be at risk of having resistance to one or more anti-VEGF agents.
49 (Provisional). The method of any of claims 34-45, wherein the individual is determined to have resistance to one or more anti-VEGF agents.
Critically, (i) the claims upon which claim 14 depends, do not recite nor require administration of ApoA-I or VEGF-antibodies at all; and (ii) claims 34-45 (or [39-49] in PCT’463), upon which claims 34, 45, and 49 each depend, do not recite nor require administration of ApoA-I or VEGF-antibodies at all. Furthermore, such disclosures pertain to a different category of patient, namely one showing “resistance to one or more anti-VEGF agents”, which is distinct from patients that are “nonresponsive” to all prior anti-VEGF therapies. Accordingly, the scope of the “wherein” clause is distinct from the closest disclosure in the priority document. The “wherein” clause in the amended claims now limits the patient population, subsequently treated with a triple therapy method including a compound of (a), (b), and (c) (including functionally defined structures at (a)(2) and (b)(2)), wherein “nonresponsive to said prior anti-VEGF therapy” is not clearly defined on record, and is not reasonably inferred to be equivalent or synonymous in scope with “nonresponsive”.
Conclusion
Guidance for determining whether or not a priority document provides written description support for pending claims is addressed at MPEP § 2163.02, which explains that
If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application.
Furthermore, per MPEP § 2163, new or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement (see, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971)). Here, the newly added claim limitations are not inherently, implicitly, or literally supported by the priority document.
Accordingly, priority to US Provisional Application 63/030421 (filed 5/27/2020) and PCT/IB2021/055463 (filed 6/21/2021) is denied for claims 1, 17, 39, 55, 60-62, and all of the dependents of those claims (e.g., all presently examined claims); these claims have been accorded latter priority date of 11/18/2022 corresponding to the filing date of US Application 17,999,348.
Withdrawn Claim Rejections
The rejection of claims 1-2, 9, 14, 17, 39, 48, 50, 52-55, 58, and 60 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, are withdrawn in view of the cancellation of claims 9, 14, 50, 52-54, and 58; and in view of the amendments to claims 1-2, 17, 48, and 55. Claims 2, 17, 48, and 55 are now withdrawn as directed to a non-elected species. The amendments filed 4/29/2026 have raised new issues under 35 USC 112(b), set forth below.
The rejection of claims 9, 14, and 48 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form, is withdrawn in view of the cancellation of claims 9 and 14, and in view of the amendments to claim 48, which is presently withdrawn as directed to a non-elected species.
The rejection of claims 1-2, 9, 14, 17, 39, 48, 50, 52-55, 58, and 60 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, is withdrawn in part in view of the cancellation of claims 9, 14, 50, 52-54, and 58; and in view of the amendments to claims 1-2, 17, 48, and 55. Claims 2, 17, 48, and 55 are now withdrawn as directed to a non-elected species. A revised rejection addressing the amended claim scope filed 4/29/2026.
The rejection of claims 1-2, 9, 14, 17, 39, 48, 50, 52-55, 58, and 60 under 35 U.S.C. 103 as being unpatentable over US2018/0125948A1 (May 10, 2018) in view of ARVO201910 as evidenced by Fu11, and further in view of NP_000030.112 and NP_658985.213, is withdrawn in part in view of the cancellation of claims 9, 14, 50, 52-54, and 58; and in view of the amendments to claims 1-2, 17, 48, and 55. Claims 2, 17, 48, and 55 are now withdrawn as directed to a non-elected species. However, the amendments and IDS filed with fee on 4/29/2026 have necessitated new rejections.
The rejection of claims 1-2, 9, 14, 17, 39, 48, 50, 52-55, 58, and 60 under 35 U.S.C. 103 as being unpatentable over US2018/0125948A1 (May 10, 2018), ARVO2019 as evidenced by Fu, NP_000030.1 and NP_658985.2 as applied to claims 1-2, 9, 14, 17, 39, 48, 50, 52-55, 58, and 60 above, and further in view of US20170283502 A1 (Oct. 5, 2017), is withdrawn in part in view of the cancellation of claims 9, 14, 50, 52-54, and 58; and in view of the amendments to claims 1-2, 17, 48, and 55; and in view of amendments excluding the originally elected species. Claims 2, 17, 48, and 55 are now withdrawn as directed to a non-elected species. However, the amendments and IDS filed with fee on 4/29/2026 have necessitated new rejections.
New, Revised, or Maintained Claim Rejections as Necessitated by Applicant Amendment
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 17, 39, 55 and 60-62 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Amended claims 1(a)(2) and 39(a)(2) now recite “a variant thereof that comprises 175 or more contiguous amino acids of SEQ ID NO: 1 and the ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization”, which renders the claim scope indefinite because this functional limitation does not literally, inherently, or implicitly appear on record, and it is therefore unclear what exact structures do or do not satisfy the functional limitation by conveying “the ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization”. Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, the claims merely recite a description of functions or results to be achieved by the invention rather than a description of the structures capable of achieving the desired functions, and therefore the claims are indefinite per MPEP § 2173.05(g). This is reasonable because MPEP § 2173 identifies that the primary purpose of the requirement is to inform the public of the boundaries of what constitutes infringement of the patent, but here it is unclear what compounds do or do not infringe upon the scope of claims 1(a)(2) and 39(a)(2). At best, the subgenus of 175 contiguous amino acids of SEQ ID NO: 1 (a 288-mer) would ostensibly include at least the 175-mer corresponding to positions 1-175, as well as the 175-mer corresponding to positions 113-288 of SEQ ID NO: 1. This is pertinent because such 175-mers only share the common structure of positions 113-175 are responsible for functionality. Positions 113-175 (63-mer) are:
VICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMT
However, zero disclosure on record or in the prior art of record reasonably identify that this minimum shared 63-mer is either necessary or sufficient to convey “the ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization” as presently claimed. Notably, the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not satisfy the functional limitations of claims 1(a)(2) and 39(a)(2), and an artisan would be unable to identify infringing from non-infringing compounds, claims 1 and 39 are rejected as indefinite.
Amended claims 1(b)(2) and 39(b)(2) now recite “a variant thereof that has 150 or more contiguous amino acids of SEQ ID NO: 3 and the ability to bind AIBP”, which renders the pending claim scope indefinite because this functional limitation does not literally, inherently, or implicitly appear on record, and therefore it is unclear what exact structures do or do not satisfy the functional limitation by conveying “the ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization”. Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, the claims merely recite a description of functions or results to be achieved by the invention rather than a description of the structures capable of achieving the desired functions, and therefore the claims are indefinite per MPEP § 2173.05(g). This is reasonable because MPEP § 2173 identifies that the primary purpose of the requirement is to inform the public of the boundaries of what constitutes infringement of the patent, but here it is unclear what compounds do or do not infringe upon the scope of claims 1(b)(2) and 39(b)(2). At best, the subgenus of sequences having 150 contiguous amino acids of SEQ ID NO: 3 (a 267-mer) would ostensibly include at least the 150-mer corresponding to positions 1-150, as well as the 150-mer corresponding to positions 117-267 of SEQ ID NO: 3. This is pertinent because such 150-mers are only required to share the common structure of positions 117-150 (i.e., a 34-mer), which are:
VKAKVQPYLDDFQKKWQEEMELYRQKVEPLRAEL
However, zero disclosure on record identifies that this minimum shared 34-mer is either necessary or sufficient to convey “the ability to bind AIBP” as required by the amended claims. Notably, the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not satisfy the functional limitations of claims 1(b)(2) and 39(b)(2), and an artisan would be unable to identify infringing from non-infringing compounds, claims 1 and 39 are rejected as indefinite.
Amended claims 1 and 39 recite the “wherein” clause “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”, which renders the claim scope indefinite because it is unclear what does or does not constitute “nonresponsive”, which is reasonably understood to be a subjective term in the prior art. Although it is clear that the “wherein” clause requires an individual to have been “previously treated with an ant-VEGF therapy” of some kind for some duration, it is unclear what the metes and bounds of “nonresponsive to said prior anti-VEGF” may be in this context. For example, if “nonresponsive” means treatment failure, then Gallenmore et al.14 discloses that “There is no universally agreed upon definition of treatment failure” for anti-VEGF therapy (see, e.g., Gallenmore at 1 at § “Recognizing Treatment Failure”), and treatment failure may range from subjectively referring to “when multiple anti-VEGF treatments have been applied and fluid or leakage persists on optical coherence tomography or fluorescein angiography” (see id), or when “vision loss continues despite a course of treatment” (see id), or when “continuous monthly injections are required to keep the macula dry or where treatment produces a decrease in edema but no improvement in vision” (see id). Critically, in the instant case, it is unclear if “nonresponsive” means complete failure (i.e., VEGF-therapy and a negative control yield indistinguishable results), or if “nonresponsive” is used to mean some intermediate level of treatment resistance (i.e., stabilization without improvement, resistance to treatment, “slow loss of efficacy . . . after repeated administration over time”, etc.). The specification does not define the metes and bounds of what does or does not constitute “nonresponsive to said prior anti-VEGF therapy”, and as evidenced by Gallenmore, treatment failure “lacks a universally agreed upon definition of treatment failure” for anti-VEGF therapy (see, e.g., Gallenmore at 1 at § “Recognizing Treatment Failure”). According the phrase “nonresponsive” is subjective in nature and is used as a functional limitation to define a patient population. Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, the “wherein” clause merely recites a subjectively defined patient population, and it is unclear what the metes and bounds of infringement for such a patient population may be as evidenced by Gallenmore. Accordingly, claims 1 and 39 are rejected as indefinite. For purposes of applying prior art, the limitation is presumed satisfied by any patient in need of combination therapies (see, e.g., Gallenmore at 6 at § Combination Therapies, Fig. 3 on 7, Figure at page 10).
Claims 17, 55, and 60-62 depend directly or indirectly from an indefinite base claim and fail to clarify the indefiniteness of the base claim. Accordingly, these claims are rejected as indefinite for the reasons applicable to the claim upon which they depend, as set forth above.
Accordingly, claims 1, 17, 39, 55 and 60-62 are rejected.
Claim Rejections - 35 USC § 112(a), New Matter
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, 39, 55, and 60-62 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.
Brief Statement of the Issues
The pending claim scope utilizes new matter and functional limitations to define the claimed invention, wherein the functional limitations fail to clearly and unambiguously correspond to a clear structure/function relationship of record or otherwise known in the prior art.
The discussion of functional limitations under 35 USC 112(b) has been discussed above, and that discussion is incorporated into the instant rejection.
Applicable Case Law
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163.
Lack of literal Support
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163.
Amended or new claims 1, 39, 48 and 60-62 lack literal support in the originally filed disclosure.
First, the combination of functional limitations and structures at claims 1(a)(2) and 39(a)(2) do not literally appear on record, wherein the subgenus of structures are defined by both a contiguous minimum length and also by a required functional limitation.
Second, the combination of functional limitations and structures at claims 1(b)(2) and 39(b)(2) do not literally appear on record, wherein the subgenus of structures are defined by both a contiguous minimum length and also by a required functional limitation.
Third, the “wherein” clause at amended claims 1 and 39 (i.e., “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”), which now limits the patient population, subsequently treated with a triple therapy method including a compound of (a), (b), and (c) (including functionally defined structures at (a)(2) and (b)(2)), wherein “nonresponsive to said prior anti-VEGF therapy” is not clearly defined on record and does not literally appear on record.
Fourth, it is unclear what amounts of any particular “variant” (see, e.g., claims 1(a)(2), 39(a)(2), 1(b)(2), 39(b)(2)) constitutes a “therapeutically effective amount” or (“effective amount”) of a composition sufficient to treat “choroidal neovascularization” as presently claimed. No structure/function relationship relating “variants” of SEQ ID NO: 1 or SEQ ID NO: 3 to “therapeutically effective amounts” is actually taught or disclosed on record commensurate in scope with the instant claims.
Lack of Implicit or Inherent Support
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163. As noted above, the claims are not literally supported by the originally filed disclosure. Accordingly, the relevant issue is whether or not the new amendments and resulting claim scope is implicitly or inherently supported by the originally filed disclosure.
Per MPEP § 2163(I)(B), “[a]n amendment to correct an obvious error does not constitute new matter where the ordinary artisan would not only recognize the existence of the error in the specification, but also recognize the appropriate correction. In re Oda, 443 F.2d 1200, 170 USPQ 268 (CCPA 1971)”. Here, no allegation that the amendments correct an obvious error has been made. Furthermore, upon inspection, Examiner is unable to identify any single “obvious error” that would lead to the instantly amended claim scope. Accordingly, the amendments cannot be said to correct an “obvious error”.
The closest supporting disclosure for the combination of functional limitations and structures of AIBP variants at claims 1(a)(2) and 39(a)(2) appears at ¶¶[0078]-[0082] of the Specification filed 11/18/2022. However, these disclosures do not literally, inherently, or implicitly correspond to the limitations at claims 1(a)(2) and 39(a)(2) because the disclosures do not pertain to structures simultaneously defined by both (i) a minimal contiguous sequence and (ii) a functional limitation requiring an unknown, minimal structure required to achieve the hoped-for and desired “ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization” as presently claimed. Regarding inherent or implicit support, 175 contiguous amino acids of SEQ ID NO: 1 (a 288-mer) would ostensibly include at least the 175-mer corresponding to positions 1-175, as well as the 175-mer corresponding to positions 113-288 of SEQ ID NO: 1. This is pertinent because such 175-mers only share the common structure of positions 113-175 (i.e., 63-mer), which has the structure:
VICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMT
However, zero disclosures on record or in the prior art identify that this minimum shared 63-mer is either necessary or sufficient to convey “the ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization” as presently claimed and required by claims 1 and 39. Rather, to the contrary, the disclosure directs artisans away from selecting any particular 63-mer, by directing artisans to numerous fragments, including 10-mers and sequences sharing only 70% identity with instant SEQ ID NO: 1 (see, e.g., Spec. filed 11/18/20221 at ¶¶[0076]-[0082]). The specification fails to identify any required, minimal sequence sufficient and necessary to convey “the ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization” as presently claimed. Rather, the document states that
Function of a polypeptide may be assessed experimentally, for example, by determining activity in an in vitro or in vivo experiment. Whether or not a given polypeptide or polynucleotide is "functional" may be determined by first selecting an appropriate function to assess.
(see, e.g., Spec. filed 11/18/20221 at ¶[0079]).
Accordingly, the original disclosure does not literally, implicitly, or inherently teach or disclose the subgenus of structures now claimed, which are defined by both a contiguous length and also by a required functional limitation, but instead discloses a laundry list of millions of structures but fail to specifically identify which structures are sufficient to convey “the ability to promote cholesterol efflux from endothelial cells and macrophages and to attenuate neovascularization” as presently claimed. Instead, the disclosure simply leaves the discovery of the structural metes and bounds of the Applicant’s claimed invention to others to “figure out” in the future (see, e.g., Spec. filed 11/18/20221 at ¶[0079]), rather than by providing a clear description of what exact structures are included or excluded by the claim scope.
The closest supporting disclosure for the combination of functional limitations and structures of ApoA-I variants at claims 1(b)(2) and 39(b)(2) in the original disclosure do not define a subgenus of ApoA-I variants by reference to both a minimum, contiguous length and also a required functional limitation as presently claimed (see, e.g., Spec. filed 11/18/20221 at ¶¶[0063]-[0064]). Although the specification teaches a contiguous length limitations (see, e.g., Spec. filed 11/18/20221 at ¶[0064]), zero guidance is provided regarding which such fragments do or do not convey “the ability to bind AIBP” as required by the instant claims. Amended claims 1(b)(2) and 39(b)(2) recites “a variant thereof that has 150 or more contiguous amino acids of SEQ ID NO: 3 and the ability to bind AIBP”, but this functional limitation does not literally, inherently, or implicitly appear on record. Notably, 150 contiguous amino acids of SEQ ID NO: 3 (a 267-mer) would ostensibly include at least the 150-mer corresponding to positions 1-150, as well as the 150-mer corresponding to positions 117-267 of SEQ ID NO: 3. This is pertinent because such 150-mers are only required to share the common structure of positions 117-150 (i.e., a 34-mer). Positions 117-150 of SEQ ID NO: 3 are as follows:
VKAKVQPYLDDFQKKWQEEMELYRQKVEPLRAEL
However, zero disclosure on record identifies that this minimum shared 34-mer is either necessary or sufficient to convey “the ability to bind AIBP” as required by the amended claims. Accordingly, there is zero literal, inherent, or implicit support for such claim scope in the priority documents because the original disclosure fails to describe which 150-mers do or do not satisfy the functional limitation required at claims 1(b)(2) and 39(b)(2).
Regarding implicit or inherent support for the “wherein” clause at amended claims 1 and 39 (i.e., “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”), the closest supporting disclosure for this clause appears at originally filed claims (11/18/2022) 14, 39, 50, and 52-54. However, none of these claims define or refer to “nonresponsive” patients, but instead to patients having or at risk of having “resistance to one or more anti-VEGF agents”, wherein “nonresponsive” and “resistance to” are different words presumed to have different meanings15. Notably, “nonresponsive” is indefinite in this context, and in view of the prior art of Gallenmore et al.16, which discloses that “There is no universally agreed upon definition of treatment failure” for anti-VEGF therapy (see, e.g., Gallenmore at 1 at § “Recognizing Treatment Failure”). Accordingly, the closest supporting disclosure does not appear to be equivalent or synonymous in scope, and zero disclosure on record meaningfully captures the “wherein” clause in the context of a patient population subsequently treated with a triple therapy method including a compound of (a), (b), and (c) (including functionally defined structures at (a)(2) and (b)(2)), as now claimed. Accordingly, the “wherein” clause does not correspond to a non-subjective patient population having a clear meaning in the prior art, and was not literally, implicitly, or inherently supported by the originally filed disclosure.
Actual Reduction to Practice
The record discloses zero examples of the claimed invention because zero examples of any triple agent combination therapy was reduced to practice “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy” as presently claimed (i.e., primary treatment is excluded by the claim scope).
Only one in vivo example of record was reduced to practice, wherein a laser-induced CNV mouse model was treated with the AIBP of SEQ ID NO: 1, apoA-1 of SEQ ID NO: 3, and a single anti-VEGF antibody of AF-493-NA (see Spec. filed 11/18/2022 at ¶¶[0133]-[0135], Figures 15E and 21; see Reply filed 10/13/2025 at 9), and wherein the components were administered via intravitreal injection17 at concentrations of 0.6-4.8µg of AIBP with a ratio of AIBP to ApoA-I of 1:4.2 (see Spec. filed 11/18/2022 at ¶[0133]).
Zero examples of the claimed methods utilizing any functionally defined “variant” of AIBP were reduced to practice or discussed with specificity.
Zero examples of the claimed methods utilizing any functionally defined “variant” of ApoA-I were reduced to practice or discussed with specificity.
Zero “therapeutically effective” or “effective” amounts were actually disclosed for any “variant” of AIBP or ApoA-I (see Spec. filed 11/18/2022 at ¶¶[0133]-[0135]).
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
As noted above, there is substantial variability in the claimed genus, which reads upon trillions of species differing by dosage, dosage frequency, patient population, AIBP structure, ApoA-I structure, and Anti-VEGF antibody structures. However, zero examples of the claimed genus of methods were reduced to practice, and zero variability was shown in either the AIBP structure, ApoA-I structures, Anti-VEGF structures, administration routes, dosage, dosage frequencies, or patient populations.
Although the MPEP does not define what constitutes a sufficient number of representative species, the Courts have indicated that the disclosure of zero species within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. Similarly, the disclosure of, at best, one species of the claimed invention, does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus.
Identifying characteristics of the genus
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
A simple threshold issue is whether or not an artisan could distinguish functionally active fragments or derivatives from non-functionally active fragments and derivatives, because the Courts have stated
“[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Upon reviewing the original disclosure, it is unclear how an artisan would reasonably distinguish infringing (i.e., “functional”) from non-infringing (i.e., non-functional) embodiments of variants of AIBP or ApoA-I as presently claimed.
The closest description of functional limitations of record is generic (see Spec. filed 11/18/2022 at ¶[0079]), and simply states
Whether or not a given polypeptide or polynucleotide is "functional" may be determined by first selecting an appropriate function to assess. For example, functionality of AIBP variants may be assessed in vitro or in vivo for the ability of the variants to attenuate neovascularization, for example, by improving removal of cholesterol from endothelial cells and/or macrophages, reducing inflammation, and/or restoring macrophages' ability to inhibit angiogenesis. Functionality of AIBP variants may also be assessed in vitro or in vivo for the ability of the variants to increase the efficacy of an anti-VEGF agent in inhibiting angiogenesis. In some cases, a functional molecule may be one that exhibits the desired function to a statistically significant degree (e.g. p<0.05; <0.01; <0.001).
Accordingly, the “functional limitation” utilized to define variants at claims 1(a)(2), 1(b)(2), 39(a)(2), and 39(b)(2) fails to correspond to any specific structure/function relationship of record. Instead of unambiguously identifying specific structures having function recited in the amended claims that Applicant desires and hopes to achieve, the disclosure merely shifts the burden of identifying such structures upon future artisans. Leaving the discovery of the metes and bounds of a functional limitation and claimed invention to future artisans does not satisfy the written description requirement because
“[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, the functional limitations of the pending claims are only utilized as a vague attempt to capture unknown and undisclosed structures, sufficient to achieve some functional result that Applicant hopes and desires that the disclosed invention is able to achieve. However, the disclosure but does not meaningfully disclose an unambiguous structure/function relationship permitting an artisan to identify, a priori, which exact structures do or do not satisfy the functional limitations at issue.
Conclusion
MPEP § 2163.02 explains that
If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application.
Furthermore, per MPEP § 2163, new or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement (see, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971)). Here, the newly added claim limitations are not inherently, implicitly, or literally supported by the priority document.
Accordingly, the claims are directed to new matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 17, 39, 55, and 60-62 are rejected under 35 U.S.C. 103 as being unpatentable over US2018/0125948A1 (May 10, 2018; cited in previous action) in view of Gallenmore et al.18, Fu19, Oral-Presentation20, NP_000030.121 and NP_658985.222.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding rejections and also in a separate section above, and those discussions and interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding claims 1(c), 17, 39(c), 55, 60, and treatment of choroidal neovascularization (CNV) in Age-related Macular Degeneration (AMD) patients by intravitreal administration of Anti-VEGF antibodies, US’948 pertains to “compositions and methods for treating CNV, such as found in the wet form of AMD, in a human subject” (see, e.g., US’948 at ¶[0005]; see also id. at ¶¶[0003]-[0005], [0023]-[0025], [0163]-[0164]; compare id. with instant claims 1, 39, and 60). US’948 explains that the routine clinical treatment of CNV in AMD patients includes intravitreal administration of anti-VEGF agents (see, e.g., US’948 at ¶¶[0004], [0168]-[0169], [0173], claims 1 and 6), wherein “anti-VEGF agents” include anti-VEGF antibodies, such as ranibizumab or bevacizumab (see, e.g., US’948 at ¶¶[0020], [0022], [0337]-[0338], claims 1, 6-9, 12, and 16-18; compare id. with instant claims 1, 39, and 60). Regarding claim 60 and the treatment of humans and animal models, US’948 identifies that laser-induced CNV animal models were known in the prior art based upon the known effects of laser photocoagulation (see, e.g., US’948 at ¶¶[0158]-[0160]). However, US’948 reasonably informs artisans that the disclosure and results are applicable to humans (see, e.g., US’948 at ¶¶[0005], [0086]-[0090]).
US’948 differs from the instant claims as follows: Although US’948 identifies that the routine clinical treatment of CNV in the wet form of AMD included intravitreal administration of anti-VEGF antibodies, US’948 does not explicitly teach or disclose the additional administration of AIBP (instant SEQ ID NO: 1) and apoA-I (i.e., instant SEQ ID NO: 3) to patients “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”.
The combination of AIBP and ApoA-I to treat CNV in AMD patients was already known and disclosed in the prior art: Fu informed artisans that “intravitreal delivery of AIBP and apoA-I robustly inhibits laser-induced CNV” in a mouse model of pathological angiogenesis (see, e.g., Fu at §§ “Purpose”, “Methods”, and “Results”). Accordingly, Fu provided clear guidance informing artisans that CNV could be predictably and desirably treated by the intravitreal delivery of human recombinant AIBP and apoA-I (see id). Accordingly, the treatment of CNV by administering the combined agents of AIBP and apoA-I was known in the prior art, shown to be therapeutically effective, and such treatment would therefore be reasonably inferred to be useful in the treatment of CNV in humans, because laser-induced CNV was an art-recognized model for human CNV (see, e.g., US’948 at ¶¶[0158]-[0160]). Likewise, Oral-Presentation pertains to the treatment of CNV in AMD patients (see, e.g., Oral-Presentation at slides 1-2), and Oral-Presentation explicitly shows that AIBP in combination with apoA-I “robustly inhibits laser-induced CNV” (see, e.g., Oral-Presentation at slides 8, 11):
PNG
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293
358
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(see, e.g., Oral-Presentation at slide 8).
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396
841
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(see, e.g., Oral-Presentation at slide 9). Oral-Presentation also provides a molecular mechanism of action explaining how AIBP treats CNV, namely AIBP “targets lipid rafts in choroidal ECs and lipid accumulation in macrophages….without affecting normal mature vessels” and inhibits angiogenesis (see, e.g., Oral-Presentation at slides 10-11). In sum, Fu and Oral-Presentation establish that the intravitreal delivery of AIBP and apoA-I was already known and taught for use in the prior art for the treatment of CNV.
Regarding instant claims 1(a)(1), 1(a)(2), 39(a)(1), 39(a)(2), 61-62, and instant SEQ ID NO: 1 and SEQ ID NO: 3: Although Fu and Oral-Presentation are silent regarding the sequences associated with AIBP and ApoA-I, Fu identifies that the proteins were “recombinant human AIBP and apoA-I” (see, e.g., Fu at § “Methods”). This is pertinent because an artisan, circa 2019, would readily appreciate that human apoA-I corresponded to the known sequence of NP_000030.1 (compare NP_000030.1 at 1, 3, and 5 with instant SEQ ID NO: 3, showing 100% identity). Furthermore, an artisan, circa 2019, would readily appreciate that human AIBP corresponded to the known sequence of NP_658985.2 (compare NP_658985.2 at 1, 4 at § Protein, and 5 with instant SEQ ID NO: 1, showing 100% identity). Therefore, in view of Fu, NP_000030.1, and NP_658985.2, and artisan would readily appreciate and understand that the prior art reasonably informed artisans that the administration of human recombinant AIBP and apoA-I corresponding to instant SEQ ID NOs: 1 and 3, could be predictably and desirably administered intravitreally to treat CNV, with the reasonable expectation that such intravitreal treatment would “robustly inhibit” CNV (see, e.g., Fu at §§ “Methods” and “Results”).
Regarding instant claims 1, 39, and the patient population “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy” was reasonably known in the prior art: Gallenmore pertains to treatment of wet AMD (see Gallenmore at title, 1 at 1st ¶), and identifies that “treatment failure” is well-known in the Anti-VEGF therapy arts for wet AMD (see id at p. 1 at 1st and 2nd full ¶¶). Gallenmore identifies that patients that had been treated with anti-VEGF therapies, unsuccessfully, existed and were well-known in the prior art, and that such patient populations included patients that had been treated with pegaptanib (see, e.g., Gallenmore at 2-3 at § Macugen Treatment Failures), or with Lucentis/Avastin (see, e.g., Gallenmore at 3 at § Lucentis, Avastin Treatment Failures). Accordingly, the patient population “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy” is understood to be fully satisfied by the patient populations indicated as “Treatment Failures” by Gallenmore.
Regarding the combination of Anti-VEGF antibodies as taught by the primary reference, and AIBP and ApoA-I as taught by Fu and Oral-Presentation: Gallenmore identifies that “Combination therapy is most commonly used … for patients failing anti-VEGF treatment” (see, e.g., Gallenmore at 6-7 at § Combination Therapies), and that combination therapies are “based on the idea that a multi-pronged approach may be more effective than any single approach since multiple factors contribute to wet AMD” (see id). Gallenmore identifies that “[a] variety of combination therapies” exist and have been utilized to treat “anti-VEGF treatment failures and in some cases as primary therapy” (see id. at 6-8). In sum, combining different wet AMD treatments to form a “combination therapy” was routine in the art, and commonly utilized to treat “anti-VEGF treatment failures”. Here, the Anti-VEGF antibody would be predicted and expected to reduce VEGF levels (see primary reference), wherein AIBP and ApoA-I would be expected to target lipid rafts in choroidal ECs and lipid accumulation in macrophages….without affecting normal mature vessels” and additionally to inhibit angiogenesis (see, e.g., Oral-Presentation at slides 10-11).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The invention is the obvious combination of known prior art treatments (i.e., Anti-VEGF antibodies, and AIBP and ApoA-I), each taught by the prior art to be useful for the same purpose of treating CNV and wet AMD, according to known methods of intravitreal administration of such compounds to patients in need thereof, in order to form a combined treatment for use for the very same purpose of treating CNV, and the idea of combining them flows logically from their having been individually taught in the prior art (see, e.g., MPEP § 2144.06(I), In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)). Furthermore, each component was known in the prior art, and would merely be expected to perform its art-recognized and disclosed functions in combination as they do separately; and per Gallenmore, it is routine in the ant-VEGF therapy arts to treat patients failing anti-VEGF treatments using combination therapies, such as a combination of Anti-VEGF antibodies, and AIBP and ApoA-I (see, e.g., MPEP § 2143(I)(A), (D), (F), (G))23.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to combine and administer known components in known treatments to a known patient population via known routes of administration, in order to achieve the results taught and suggested by the prior art (i.e., treatment of CNV) with a reasonable expectation of success.
Accordingly, claims 1, 17, 39, 55, and 60-62 are rejected.
Response to Arguments
Applicant’s arguments with respect to claims 1, 17, 39, 55, and 60-62 have been considered but are substantially rendered moot in view of the new and revised grounds of rejection set forth above. Remaining applicable arguments are addressed below.
Allegation that “therapeutically effective amount” or “effective amount” is definite language and therefore has written description support: It is the Examiner’s understanding that Applicant conflates the requirements of 35 USC §112(a) and 35 USC §112(b), because Applicant addresses a written description rejection by alleging that “a skilled artisan would find the term definite as being therapeutic for the indication” (see, e.g., Reply filed 4/29/2026 at § VIII at 17-18). Definiteness and written description support are two materially different issues, which have different requirements. Here, the originally filed disclosure fails to provide guidance regarding what constitutes a therapeutically effective amount of the untested “variants” presently claimed, and do not address what variants satisfy the functional limitations set forth in the amended claims. Accordingly, “therapeutically effective” is used by Applicant to attempt to capture subject matter they hope and wish to achieve (i.e., all amounts of such variants and combinations thereof that are “therapeutically effective”), but no corresponding description of record is commensurate in scope with such functional limitations. A revised rejection under 35 USC 112(a) has been necessitated by the amendments filed 4/29/2026.
Allegation that a claim limitation added 4/29/2026 was not considered in the Action mailed 12/31/2025: It is the Examiner’s understanding that Applicant is alleging that the amended claims overcome the rejection of record because that rejection did not address a subsequently added limitation with respect to the patient population and newly added “wherein” clause (see, e.g., Remarks filed 4/29/2026 at 18-19 at § IX.A). This is neither disputed nor dispositive of patentability. The amended claim scope filed 4/29/2026 has necessitated new and revised rejections. The limitation regarding patient populations is addressed in view of Gallenmore, which discloses that “combination therapies” were commonly used in the Anti-VEGF therapy arts to treat patients failing anti-VEGF treatments (see, e.g., Gallenmore at 6-7 at § Combination Therapies).
Examiner is permitted to establish obviousness using any rationale set forth at MPEP §2143 and §2144: It is the Examiner’s understanding that Applicant alleges that there was no motivation to combine the known CNV therapy of Anti-VEGF antibodies with the known CNV therapy of administering AIBP/ApoA-I to form a combined method for the treatment of CNV (see, e.g., Reply filed 4/29/2026 at 19-21 at § IX.B). It is the Examiner’s understanding that Applicant’s basis for this allegation is that the Applicant had a different reason for combining the known treatments based upon “macrophage cholesterol efflux” (see id. at 20 at 1st full ¶). This is not persuasive because an examiner may support a determination of obviousness by relying upon a rationale that differs from the Applicant’s rationale (see, e.g., MPEP § 2144(IV)). Here, the Examiner’s rationales are explicitly identified in the rejection (see, e.g., MPEP § 2144.06(I), In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980), MPEP §§ 2143(I)(A), (D), (F), and (G)). Per KSR, all that is needed to sustain a determination of obviousness is:
A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007).
"[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007) (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273 , 282 , 96 S. Ct. 1532 , 47 L. Ed. 2d 784 (1976)).
Here, all components were known in the prior art, the function of each component was known in the prior art, the patient population was known in the prior art, and one of skill in the art could combine such known components, and such combination yields “no more than one would expect from such an arrangement”, namely the successful treatment of CNV in a patient following Anti-VEGF monotherapy failure. Accordingly, a clear rationale for supporting a determination of obviousness has been placed on record.
Allegations suggesting the references “teach away”: It is the Examiner’s understanding that Applicant is suggesting that the references “teach away” from the claimed invention in view of the statements alleging that US’948 discloses additional treatments, including gene therapy (see, e.g., Reply filed 4/29/2026 at 19-21 at § IX.B). Examiner notes that this argument is not persuasive because none of prior art references at issue “teach away” from the claimed invention since they do not actually “criticize, discredit, or otherwise discourage the solution claimed” (see, e.g., MPEP § 2141.02(VI)). Accordingly, no “teaching away” has been identified on record. Furthermore, Examiner notes that the pending claim scope recites “comprising” language and therefore does not exclude gene therapy steps.
Allegation that mechanism of action of AIBP/ApoA-I was unknown in the prior art: It is the Examiner’s understanding that Applicant incorrectly alleges that “it required the recognition of a previously unknown resistance mechanism and the identification of a structurally and mechanistically unrelated agent capable of addressing [cholesterol efflux]” (see, e.g., Reply filed 4/29/2026 at § IX.B at 20 at 1st full ¶). It is unclear what factual support exists that supports this assertion because Fu and Oral-Presentation are prior art references that unambiguously teach the successful usage of AIBP/ApoA-I in the treatment of CNV, wherein the mechanism of action is clearly identified in the title of Fu and the slides of Oral-Presentation (see, e.g., Fu at title, stating “AIBP suppresses choroidal neovascularization (CNV) by enhancing cholesterol efflux”). Accordingly, arguments premised upon ignoring facts of record are not persuasive.
Allegations that unclaimed limitations were not considered: It is the Examiner’s understanding that Applicant repeatedly refers to unclaimed limitations (see, e.g., Reply filed 4/29/2026 at 19-21 at § IX.B, referring to “macrophage cholesterol efflux”, “cholesterol transport modulator acting on macrophages”, etc.; see also Reply filed 4/29/2026 at 20-21 at § IX.C, referring to “young, non-resistant mouse model”, “restore efficacy”, etc.). Although it is undisputed that all words in a claim must be considered (see, e.g., MPEP § 2143.03(I)-(II)), arguments premised upon allegations that references fail to show certain features of the invention that are not actually recited in the rejected claims are not persuasive. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Accordingly, such arguments are not persuasive.
Arguments addressing references individually where the rejection is based upon a combination of references: It is the Examiner’s understanding that Applicant repeatedly addresses the teachings of a single reference in isolation rather than in combination (see, e.g., Reply filed 4/29/2026 at 19-21 at § IX.A, addressing US’948 alone). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Allegations suggesting “lack of predictability” or “lack of reasonable expectation of success”: It is the Examiner’s understanding that Applicant is alleging a lack of predictability or otherwise a lack of reasonable expectation of success because “a POSA would have required either empirical evidence or a recognized mechanistic basis to predict that the combination would restore efficacy” (see, e.g., Reply filed 4/29/2026 at 20-21 at § IX.C). First, the mechanistic basis of action for each component was already disclosed and known in the prior art, and Applicant has failed to identify a single component with an unknown mechanistic basis since Fu and Oral-Presentation are both prior art references. Second, empirical results do in fact exist showing that Anti-VEGF antibodies and the combination of AIBP/ApoA-I do, in fact, treat CNV (see rejections, above). Third, Applicant’s assertions do not reflect the proper legal standards for evaluating predictability. MPEP § 2143.02(II) explains that “[o]bviousness does not require absolute predictability”, but instead clarifies that only “at least some degree of predictability is required” (see, e.g., MPEP § 2143.02(II)). Here, the rejection explicitly addresses predictability and reasonable expectation of success, but Applicant fails to address the explicitly identified predicted and expected results set forth in the rejection. Here, the Examiner’s basis for “predictability” is merely based upon the presumption that the prior art is fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). As explained at MPEP § 2143.02, predictability and reasonable expectation of success are satisfied when “all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art”. Here, the predicted and expected results of combining known CNV treatments would be a combination capable of successfully treating CNV. As explained in detail below, zero evidence of unexpected results commensurate in scope with the requirements of MPEP 716.02 have been set forth on record, all elements of the claimed invention were known in the prior art, one of ordinary skill was fully enabled to combined each component using routine methods in the biochemical arts per the guidance of the primary reference, and the elements would have merely performed their art-recognized, respective functions (see Rejection, above)..
Arguments premised upon data not in the public domain either at the time the invention was made (pre-AIA ) or before the effective filing date of the claimed invention (AIA ): It is the Examiner’s understanding that Applicant is alleging that prima facie obviousness was not established based upon data that was not publicly available either at the time the invention was made (pre-AIA ) or otherwise before the effective filing date of the claimed invention (AIA ) (see, e.g., Reply filed 4/29/2026 at 20-21 at § IX.C, referring to “two agents that are each ineffective in the resistant model”; 21-23 at § IX.D, referring to Figure 15E as “the resistant model” and alleging “There was no reasonable expectation ….[of success]”). If Applicant is attempting to rebut the Examiner’s determination of prima facie obviousness based upon the instant disclosure and/or post-filed publications, this is improper and not persuasive because predictability is based upon the public domain at the relevant time (see, e.g., MPEP § 2143.02(III)), and instant Figure 15E (“the resistant model”) was not in the prior art at the time of the invention. Accordingly, relying upon teachings only available in the public domain post-filing is analogous to improper hindsight reasoning since such “illustrat[ion] of unpredictability” was not available in the applicable prior art. Accordingly, such evidence does not rebut a determination of prima facie obviousness in view of the prior art (see, e.g., MPEP § 2143.02(III)).
Allegations suggesting “inoperability” or lack of enabling disclosure regarding a prior art reference: It is the Examiner’s understanding that Applicant’s statements amount to a suggestion that the prior art is not fully enabled or operable for the treatment of a “resistant” mouse model (see, e.g., Reply filed 4/29/2026 at 20-21 at § IX.C, referring to “two agents that are each ineffective in the resistant model”; 21-23 at § IX.D, referring to Figure 15E as “the resistant model”). If Applicant is attempting to allege that the prior art is not enabling or inoperable Applicant is directed to MPEP § 2121(I), which notes that the prior art is presumed fully enabled for all that it discloses, and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I); MPEP § 716.07). No evidence of inoperability commensurate in scope with the requirements of MPEP § 716.07 have been placed on record at this time; critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), and evidence is required to rebut the presumption of operability. The Examiner’s position is that the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)). Here, in direct contrast to Applicant’s premise, Oral-Presentation and Fu represent publicly available data at the relevant time for considering obviousness, and these prior art documents clearly show that AIBP and ApoA-I successfully treat CNV in both “Young mice” and “Older mice”:
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(see, e.g., Oral-Presentation at slide 9). Accordingly, the evidence available in the prior art would have directed an artisan to conclude that such treatments would be successful in “older mice”. Accordingly, the Applicant has not satisfied their burden to rebut the presumption of operability of the prior art at this time (see, e.g., MPEP § 2121(I); MPEP § 716.07).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §716 have been placed on record: It is the Examiner’s understanding that Applicant repeatedly alleges the existence of unexpected results commensurate in scope with the requirements of MPEP §716, §716.01, and §716.02, wherein such results are sufficient to rebut prima facie obviousness (see, e.g., Reply filed 4/29/2026 at 21-23 at § IX.D and 23 at § IX.E). However, to establish such unexpected results, the allegations must be timely and supported by objective evidence (see, e.g., 37 C.F.R. 1.132; see MPEP §§ 716.01, 716.01(a), 716.01(c)); to be of probative value the proffered evidence must be related to the claimed invention (see MPEP §§ 716.01(b), discussing nexus requirement and noting that "[w]here the offered secondary consideration actually results from something other than what is both claimed and novel in the claim, there is no nexus to the merits of the claimed invention"); the evidence must establish that the expected results occur to an unexpected extent (see, e.g., MPEP § 716.02(a)(I)), on the basis of statistically and practically significant evidence (see, e.g., MPEP § 716.02(b)(I)), which is fully explained (see, e.g., MPEP § 716.02(b)(II)), commensurate in scope with the claimed invention (see, e.g., MPEP § 716.02(d)), and wherein a comparison of the claimed invention with the closest prior art of record is provided (see, e.g., MPEP § 716.02(e)). Furthermore, even if evidence satisfying MPEP §§ 716.02, 716.02(a), 716.02(b), 716.02(d), and 716.02(e) is set forth on record, such evidence may not be sufficient to rebut prima facie obviousness because the evidence of expected and unexpected results must be weighed (see, e.g., MPEP § 716.02(c)(I)) and the totality of the record considered (see, e.g., MPEP §§ 716.01(d), 716.02(f)), including teachings in the prior art and evidence of expected results which weigh in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II)). Here, the allegations of unexpected results are understood to be premised upon the Declaration filed 4/26/2026 (see, e.g., Reply filed 4/29/2026 at 21 at penultimate ¶), and therefore the analysis of the proffered data has been set forth below in a separate section. In brief, the proffered data is insufficient to establish unexpected results at least because the proffered data is not commensurate in scope with the instant claims as required by MPEP § 716.02(d), as zero variants as recited at claims 1(a)(2), 1(b)(2), 39(a)(2), or 39(b)(2) were tested at all, and the claim scope is not limited to laser-induced CNV in 18-month old male mice; and the proffered data appear to show the expected results, namely that the combination of prior art agents do, in fact, treat CNV, exactly as expected, which weighs in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II)). In addition, Applicant incorrectly identifies that the “Anti-VEGF monotherapy represents the closest prior art comparator”, which is factually incorrect. Oral-Presentation shows that ApoA-I and AIBP were tested in combination, and that combination is the closest prior art of record (see rejection, above), and zero statistically significant results relative to the closest prior art of record have been shown by Applicants as required by MPEP § 716.02(b), § 716.02(e), and 716.02(e)(II). Accordingly, no evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Applicant takes inconsonant positions regarding required empirical and mechanistic evidence required: It is the Examiner’s understanding that Applicant alleges that the combination of three known compounds, each taught by the prior art for use in the treatment of CNV, for use in a combined method of treating CNV requires “empirical evidence or a recognized mechanistic basis” (see, e.g., Reply filed 4/29/2026 at 20-21 at § IX.C), but subsequently takes the position that the limited data of record is commensurate in scope with the instant claims (see, e.g., Reply filed 4/29/2026 at 23 at § IX.E) based upon zero empirical evidence of any activity, and zero evidence-based structure/function relationships of record. Examiner has reviewed the allegations that the disclosure is commensurate in scope with the pending claim scope (see, e.g., Reply filed 4/29/2026 at 23 at § IX.E), but is not persuaded because the claimed subgenus of variants defined by both a minimum contiguous length and a required function constitute new matter. Furthermore, all statements appear to be arguments of counsel unsupported by any objected evidence that merely recite assumptions (see, e.g., Reply filed 4/29/2026 at 23 at § IX.E). Rather, the proffered data tests zero variants as recited at claims 1(a)(2), 1(b)(2), 39(a)(2), or 39(b)(2), and provides zero guidance of what does or does not constitute “therapeutically effective” concentrations of such variants.
Accordingly, all applicable arguments have been fully considered but not found persuasive. The amended claim scope does not currently define patentable subject matter as established by the new rejections set forth above. All new rejections were necessitated by Applicant’s amendments and IDS filed 4/29/2026 submitted with the fee.
Response to Declaration under 37 C.F.R. §1.132 by Fu
The affidavit under 37 CFR 1.132 filed 4/29/2026 is insufficient to overcome the rejections of the examined claims as set forth in the instant Office action. A detailed explanation of why the affidavit or declaration is insufficient is provided below. The legal standards of review and consideration of Declaration under 37 C.F.R. §1.132 are discussed at MPEP § 716.01.
Interest of the Expert in the Outcome of the Case
Per MPEP 716.01(c)(III), in assessing the probative value of an expert opinion, the examiner must consider the interest of the expert in the outcome of the case. Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 227 USPQ 657 (Fed. Cir. 1985), cert. denied, 475 U.S. 1017 (1986). Here, the Declarant is a named inventor (see, e.g., Dec. at ¶¶1-6) and therefore has a clear interest in the outcome of the case.
Nature of the Matter Sought to be Established
Per MPEP 716.01(c)(III), in assessing the probative value of an expert opinion, the examiner must consider the nature of the matter sought to be established. Ashland Oil, Inc., 776 F.2d 281. Here, the Declarant is attempting to establish unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 (see, e.g., Dec. at ¶¶10-29, 35-38, 41-45), legal opinions regarding obviousness (see, e.g., Dec. at ¶¶30-34), legal opinions regarding written description support (see, e.g., Dec. at ¶¶39-40), and evidence that an unclaimed species is not enabled or operable in view of the prior art (see, e.g., Dec. at ¶¶10-29, 35-38, 41-45).
Opinions as to Legal Conclusions
As an initial matter, Examiner notes that per MPEP 716.01(c)(III), any opinions expressed by Declarant regarding legal conclusions are not entitled to any weight. However, the underlying basis for any opinion as to legal conclusions has been fully considered as detailed below.
Presence or absence of factual support for the expert’s opinion
Per MPEP 716.01(c)(III), in assessing the probative value of an expert opinion, the examiner must consider the presence or absence of factual support for the expert’s opinion. Ashland Oil, Inc., 776 F.2d 281.
No Unexpected Results Established
To establish unexpected results, the proffered data must be commensurate in scope with the requirements set forth at MPEP §§ 716, 716.01, and 716.02. Following review, the proffered evidence fails to satisfy these requirements, and therefore the proffered declaration does not establish unexpected results sufficient to rebut prima facie obviousness.
Per MPEP § 716.01(b) the proffered data must share a nexus with the claimed invention. MPEP § 716.01(b) discusses the Nexus requirement, and explains that “To be of probative value, any secondary evidence must be related to the claimed invention”, and “If the evidence is to be given substantial weight in the determination of obviousness or nonobviousness, evidence of secondary considerations must be relevant to the subject matter as claimed”, wherein “Applicant or patent owner bears the burden of establishing a nexus between the objective evidence of nonobviousness and the claimed invention”, and "Where the offered secondary consideration actually results from something other than what is both claimed and novel in the claim, there is no nexus to the merits of the claimed invention." Here, the only aspect that appears “both claimed and novel” is the newly added limitation to the patient population, namely the “wherein” clause reciting “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”. However, this is problematic because it is unclear that 18-month old male mice with laser-induced CNV actually share any nexus to the patient population defined by the “wherein” clause at claims 1 and 39:
First, the “wherein” clause has been rejected under 35 USC §112(a) and §112(b) as indefinite and lacking written description support (see rejections above). The meaning of “nonresponsive” in this context is not clearly disclosed on record, which is problematic because “treatment failure” in the anti-VEGF therapy arts is understood to be subjective, and the art “lacks a universally agreed upon definition of treatment failure” for anti-VEGF therapy (see, e.g., Gallenmore at 1 at § “Recognizing Treatment Failure”, noting that treatment failure “lacks a universally agreed upon definition of treatment failure” for anti-VEGF therapy). Accordingly, it is unclear if “nonresponsive” means complete treatment failure (i.e., VEGF-therapy and a negative control yield statistically indistinguishable results), or if the term is used subjectively to refer to situations “when multiple anti-VEGF treatments have been applied and fluid or leakage persists on optical coherence tomography or fluorescein angiography” (see id), or when “vision loss continues despite a course of treatment” (see id), or when “continuous monthly injections are required to keep the macula dry or where treatment produces a decrease in edema but no improvement in vision” (see id), or something else entirely. Therefore, it is unclear if the experimental model shares a clear nexus with the pending claim scope.
Second, Declarant admits that “No suitable animal models for studying anti-VEGF resistance in CNV had been widely validated” (see, e.g., Dec. at ¶9), but then Declarant fails to identify or explain how the proffered model was actually clinically validated as equivalent to the claimed patient population by providing any actual objective evidence that the claimed invention (and “wherein” clause) corresponds to an 18-month old male mouse model rather than an 8-month old male mouse model, which shows opposite results of the 18-month model.
Third, the nexus and relevance of the animal model to the claimed invention is questionable because the basis for the Applicant’s arguments is understood to rest upon Figure 15E, which allegedly shows that the prior art combination of ApoA-I and AIBP was not therapeutically effective in 18-month old male mice (see, e.g., Dec. at ¶¶10-13, 15-18, 42), but such assertions do not address the relevance of Figures 15C and 15D to the pending claim scope, which is critical because such figures show that ApoA-I/AIBP combination treatment was, in fact, therapeutically effective in 6-8 week mice (Fig. 15C) and 8-month mice (Fig. 15D):
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Accordingly, it is unclear why the 18-month old mice, but not the 8-month old mice are representative of the claimed patient population.
Fourth, the patient population defined by the clause “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy” requires that the patient was “previously treated”, which excludes primary therapy (see, e.g., Gallenmore at 7 at 1st ¶, explaining that combination therapies can be utilized after “anti-VEGF treatment failures” or alternatively “as primary therapy”). Here, all proffered data pertains to primary therapy wherein the same animals were not previously treated with anti-VEGF Therapy. This distinction limits the prior art available to establish obviousness, but this limitation has not been recapitulated in the proffered animal model. Therefore, the shared nexus of the proffered data with the claimed invention is questionable because the data pertains to primary therapies and therefore does not reflect what is “both claimed and novel in the claim” as required to establish a nexus.
Per MPEP § 716.01(b), the Applicant or patent owner bears the burden of establishing a nexus between the objective evidence of nonobviousness and the claimed invention. This burden has not been met because there is no evidence showing a nexus between 18-month old male mice with laser-induced CNV given primary therapy, and the actual claimed patient population of claims 1 and 39, “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”. Rather, the claimed invention and patient population as claimed appears to be equally close to treatment of 8-month old mice with laser-induced CNV given primary therapy. Per MPEP § 716.01(b), "Where the offered secondary consideration actually results from something other than what is both claimed and novel in the claim, there is no nexus to the merits of the claimed invention", and here the secondary consideration reasonably appears to result from limitations of the model system utilized, wherein the difference between 18-month old mice and 8-month old mice is not reasonably reflected by the claimed limitation “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”. Accordingly, the proffered data fails to establish a clear nexus with the claimed invention.
The closest prior art is not correctly identified: Declarant incorrectly identifies that “Anti-VEGF monotherapy” represents the closest prior art comparator (see, e.g., Dec. at ¶¶13-14). Per MPEP § 716.02(e), a declaration “must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness”, and per MPEP § 716.02(e)(II), “showing unexpected results over one of two equally close prior art references will not rebut prima facie obviousness”. Here, Fu and Oral-Presentation show that ApoA-I and AIBP were tested in combination, and therefore the combination of ApoA-I and AIBP is either the closest prior art of record, or otherwise equally close (see rejection, above). Therefore, “Anti-VEGF monotherapy” is not the closest comparator of record, and therefore evidence sufficient to satisfy the requirements set forth at MPEP § 716.02 must show a statistically significant difference relative to the prior art combination of ApoA-I and AIBP to satisfy MPEP § 716.02(b), § 716.02(e), and 716.02(e)(II). For these reasons, the data shown at Exhibit 2(A), 2(B), Fig. 16, and related arguments, are not persuasive because such data does not actually test or provide a comparison of the claimed invention with the closest prior art of record.
The proffered data does not satisfy the requirement of MPEP § 716.02(b): Declarant incorrectly alleges that “Administration of AIBP and apoA-I in the absence of an anti-VEGF agent also produced no statistically significant suppression of CNV in the resistant model (FIG. 15E)” (see, e.g., Dec. at ¶¶17-18). However, as shown by Figure 15E (reproduced below)
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no indication that any statistically significant difference between the “AIBP+apoA1” sample (i.e., the closest prior art of record) and the “AIBP+apoA1+anti-VEGF (low)” sample is actually shown at Figure 15E, as indicated by the absence of any horizontal bar with either “*” or “NS” between those samples. Rather, the available statistically data of record shows that ApoA-I/AIBP combination treatment was, in fact, statistically significant and therapeutically effective in 6-8 week mice (Fig. 15C) and 8-month mice (Fig. 15D):
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Accordingly, references to Figure 15E establishing a lack of statistically significant therapeutic effect for “AIBP+apoA1” sample (see, e.g., Dec. at 17-18) is unsupported by objective evidence commensurate in scope with the requirements of MPEP § 716.02(b), § 716.02(e), and 716.02(e)(II). Furthermore, assertions of statistical significance in the absence of evidence does not satisfy Declarant’s burden under MPEP § 716.02(b)(II), because Declarant fails to explain why the lack of evidence of statistical analysis would be interpreted as a lack of statistical significance.
The proffered data does not satisfy the requirement of MPEP § 716.02(e), because the proffered evidence shows a comparison of two unclaimed inventions (i.e., primary treatment of an 18-month old mouse model), but MPEP § 716.02(e)(I) and (III) require a comparison of “the claimed invention”. Here, as explained above, the clause at claims 1 and 39 recite and require “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy”. Therefore, the pending claims require that the patient was “previously treated”, which excludes primary therapy from the scope of claims 1 and 39 (see, e.g., Gallenmore at 7 at 1st ¶, explaining that combination therapies can be utilized after “anti-VEGF treatment failures” or alternatively “as primary therapy”). Therefore, the pending claims exclude the embodiments utilized in the proffered data, because the “wherein” clause requires a previous treatment, not primary treatment. If Applicant wishes to claim primary treatment methods, the claim scope should be so amended, and examination will be extended to consider such treatment methods.
The proffered data does not satisfy the requirement of MPEP § 716.02(d), the proffered data at Figure 15E reflects a highly limited subset of data, namely exact substances (i.e., SEQ ID NO: 1, SEQ ID NO: 3, and the Anti-VEGF antibody of “AF-493-NA”24, tested at static doses, in a primary therapy treatment of an 18-month old male mouse laser-induced CNV model (see, e.g., Fig. 15E; see Dec. at ¶¶10-16). However, the claim scope is not limited to primary therapy treatments, is not limited to combinations of SEQ ID NO: 1, 3, and AF-493-NA. Zero data is provided testing any variants or alternative compositions within the scope of instant claims 1 and 39, with any other patient population within the scope of the “wherein” clause at instant claims 1 and 39. Examiner notes that Declarant alleges that the proffered data is commensurate in scope with the pending claims (see, e.g., Dec. at ¶¶35-38), but zero objective evidence supporting such conclusion is actually provided on record. Rather, Declarant refers to hoped-for and desired functions that Declarant wants such variants to achieve (see, e.g., Dec. at ¶¶35-38 , referring to “derivatives that retain AIBP biological activity”, “variants of AIBP that retain biological activity”, etc.), but Declarant fails to actually identify what structures within the scope of instant claims 1(a)(2), 1(b)(2), 39(a)(1), and 39(a)(2) are (or are not) capable of conveying such functionality. Although Declarant identifies that the original disclosure provides “functional screening criteria” (see, e.g., Dec. at ¶37), a disclosure of screening criteria evidences possession of screening criteriaunder 35 USC 112(a), but does not evidence possession or written description support for all compounds discoverable by such screen. Accordingly, such variants were not tested or reasonably disclosed in view of the instant record. Accordingly, the proffered data does not satisfy the requirements of MPEP § 716.02(d).
The proffered data supports a conclusion of obviousness per MPEP § 716.02(c)(II), which states that "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." Here, the prior art of record, including Fu and Oral-Presentation, establish that the combination of AIBP+ApoA-I can successfully treat CNV in older mice, and that AIBP in combination with apoA-I “robustly inhibits laser-induced CNV” (see, e.g., Oral-Presentation at slides 8, 11):
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(see, e.g., Oral-Presentation at slide 8).
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(see, e.g., Oral-Presentation at slide 9). Oral-Presentation also provides a molecular mechanism of action explaining how AIBP treats CNV, namely AIBP “targets lipid rafts in choroidal ECs and lipid accumulation in macrophages….without affecting normal mature vessels” and inhibits angiogenesis (see, e.g., Oral-Presentation at slides 10-11). Accordingly, at the time of filing the instant Application, an artisan would have readily predicted and concluded that AIBP+ApoA-I could successfully treat CNV in older mice exactly as shown in the proffered data. Accordingly, the combination of AIBP+ApoA-I and an Anti-VEGF antibody would have been predicted and expected, in view of the prior art, to successfully treat CNV in older mice exactly as suggested in view of the prior art. Critically, the proffered data shows this exact result, namely that the combination of AIBP+ApoA-I and an Anti-VEGF antibody does, in fact, successfully treat CNV in older mice exactly as taught and suggested in view of the prior art of record. The fact that Declarant identifies that the prior art may not be fully enabled for treatment of an unclaimed embodiment (i.e., treatment of CNV with AIBP+ApoA-I in an 18-month old mouse with laser-induced CNV), does not alter the predicted and expected results in view of the prior art (see, e.g., MPEP 2121.01(II), 2143.02(III); see also MPEP § 716.07). Rather, outcome claimed (i.e., the combination of AIBP+ApoA-I and an Anti-VEGF antibody does, in fact, successfully treat CNV in older mice) remains the exact same as taught and suggested by the prior art. This weighs in favor of a determination of obviousness per MPEP § 716.02(c)(II).
In sum, no showing of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record at this time because the proffered data does not satisfy the requirements of MPEP §§ 716.01(b), 716.02(b), 716.02(d), 716.02(e), or 716.02(e)(II).
Opinions as to Legal Conclusions
It is the Examiner’s understanding that Declarant provides opinions as to legal conclusions of obviousness (see, e.g., Dec. at ¶¶30-34) and written description (see, e.g., Dec. at ¶¶39-40). Examiner notes that per MPEP 716.01(c)(III), any opinions expressed by Declarant regarding legal conclusions are not entitled to any weight. However, the underlying basis for any opinion as to legal conclusions has been fully considered as detailed below.
It is the Examiner’s understanding that Declarant provides opinions regarding the teachings of the prior art (see, e.g., Dec. at ¶¶30-34). The Declarant does not address the rejection at issue or the teachings of Oral-Presentation. Furthermore, Declarant addresses the teachings of the references in isolation rather than in combination. Declarant appears to mistakenly suggest that the instant claim scope excludes gene therapy (see, e.g., Dec. at ¶¶31), but the claim scope is open-ended and does not exclude steps of gene therapy. Declarant appears to allege that they have a different reason for reaching the claimed invention (see, e.g., Dec. at ¶¶30-34). This does not refute obviousness because the Examiner may rely upon a rationale that differs from the Applicant’s rationale (see, e.g., MPEP 2144(IV)), and here the Examiner’s rationale is explicitly identified in the rejection. The arguments raised appear to substantially mirror arguments addressed above and raised by Applicant, and therefore the Examiner’s response above is incorporated herein. In addition, such opinions are moot because they fail to address the new rejection and art of record, necessitated by the recently filed amendments.
It is the Examiner’s understanding that Declarant opines that, in their personal opinion, the as-filed specification satisfies the requirements of 35 USC 112(a), for written description (see, e.g., Dec. at ¶¶39-40). Per MPEP 716.01(c)(III), any opinions expressed by Declarant regarding legal conclusions are not entitled to any weight. However, the underlying basis for any opinion as to legal conclusions has been considered herein. The basis for the Declarant’s opinion appears to be the disclosure of full-length SEQ ID NO: 1, SEQ ID NO: 3, “a working example of the claimed combination in the elected species”, and the alleged disclosure of “functional screening criteria for identifying active AIBP variants” (see, e.g., Dec. at ¶¶39-40). This is insufficient to establish support commensurate in scope with 35 USC 112(a), because: (A) Possession of SEQ ID NOs: 1 and 3 do not evidence possession of functional variants of either sequence; (B) zero working examples of the claimed invention were reduced to practice on record because zero species “wherein the individual has been previously treated with an anti-VEGF therapy and is nonresponsive to said prior anti-VEGF therapy” were reduced to practice; (C) even assuming arguendo that one species was reduced to practice, the possession of one species does not support possession of all species within the scope of claims 1 and 39, because those claims are not limited to the structures utilized in that species; (D) the alleged disclosure of “functional screening criteria for identifying active AIBP variants” (see, e.g., Dec. at ¶¶39-40) does not support a conclusion of possession of all possible AIBP variants discoverable by such method, and fails to pertain to ApoA-I variants as currently claimed. MPEP 2163(II)(A)(3)(a), explains that “describing a composition by its function alone typically will not suffice to sufficiently describe the composition”, (see Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406, holding that description of a gene’s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is”), and explaining that a description for screening compounds does not provide written description support for discoverable compounds (see, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004), The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described."). Accordingly, disclosure of “screening criteria” is insufficient to provide written description support. Accordingly, the basis for the Declarant’s legal opinion has been fully considered but not found persuasive for the reasons discussed above, and for the reasons set forth in the new rejections of record, as necessitated by Applicant’s amendments.
It is the Examiner’s understanding that Declarant attempts to allege that the “prior art cited by the Examiner does not disclose, suggest, or predict the observed restoration of efficacy” (see, e.g., Dec. at ¶44).
First, if Declarant is suggesting that prima facie obviousness was not established based upon data that was not publicly available either at the time the invention was made (pre-AIA ) or otherwise before the effective filing date of the claimed invention (AIA ) (see, e.g., Dec. at ¶44), this is improper and not persuasive because predictability is based upon the public domain at the relevant time (see, e.g., MPEP § 2143.02(III)), and instant Figure 15E (“the resistant model”) was not in the prior art at the time of the invention. Accordingly, relying upon teachings only available in the public domain post-filing is analogous to improper hindsight reasoning since such “illustrat[ion] of unpredictability” was not available in the applicable prior art. Accordingly, such evidence does not rebut a determination of prima facie obviousness in view of the prior art (see, e.g., MPEP § 2143.02(III)). Notably, all data within the public domain (e.g., Fu and Oral-Presentation) suggest and establish that the combination of ApoA-I and AIBP could be utilized successfully to treat CNV in older subjects.
Regarding “restoration of efficacy”, this is not a claimed limitation. Furthermore, although it may be the Declarant’s rationale for arriving at the claimed invention, it is not the Examiner’s rationale (see, e.g., MPEP § 2144(IV), explaining that an examiner does not have to utilize an Applicant’s rationale to support a determination of obviousness). Here, the rejection of record explains that all components were known in the art, including an overlapping patient population, and discloses that such patients were routinely treated with combination therapies. Accordingly, an artisan would have been motivated, without any knowledge gleaned from the instant disclosure, to combine known agents for treating CNV to arrive at a combination therapy for treating CNV, and the idea of combining them flows logically from their having been individually taught in the prior art (see, e.g., MPEP § 2144.06(I), In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)) 25.
Therefore, such arguments do not rebut prima facie obviousness.
Evidence of Inoperability of an Unclaimed Method
Upon review of the Declaration, it is the Examiner’s understanding that Declarant is alleging that the unclaimed method of treating 18-month old male mice with laser-induced CNV with just AIBP and ApoA-I (no Anti-VEGF antibody) is inoperable in view of Figure 15E. This evidence has been fully considered under MPEP § 716.07. Notably, the rejection is premised upon a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Accordingly, in the light most favorable to the Applicant, if Figure 15E is deemed to identify that such treatment is inoperable, it is unclear how this would weigh in favor of a determination of allowability of the claimed invention, which is not limited to administration of a primary therapy of just AIBP and ApoA-I (no Anti-VEGF antibody) in 18-month old male mice with laser-induced CNV. Even if this evidence, which was not in the prior art, was deemed to successfully render the unclaimed method unenabled, the prior art would still be deemed operable and enabling for all other embodiments disclosed, taught, or fairly suggested (see, e.g., MPEP § 2121(I), §§ 2123(I)-(II)), which would include administration of AIBP and ApoA-I to “older mice” to successfully treat CNV. In sum, reliance upon Figure 15E to suggest that an unclaimed embodiment that was not known in the prior art was not enabled for treatment of CNV using just AIBP and ApoA-I, would alter the expectations of the prior art regarding claimed subject matter based upon evidence known in the prior art, is misplaced.
Weighing Objective Evidence
Per MPEP § 716.01(d), the ultimate determination of patentability must be based on consideration of the entire record and notes that submission of evidence of patentability does not mandate a conclusion of patentability in and of itself. Here, no statistically significant showing of unexpected results between the claimed invention and the closest prior art of record has been set forth for the reasons discussed above.
Therefore, in view of the record as a whole, the Declaration is insufficient to overcome the rejections of record.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US20170283502 A1 (Oct. 5, 2017; cited in previous action) identifies that, circa 2017, AF-493-NA was a prior art element, namely an art-recognized anti-VEGF antibody (“VEGF neutralizing antibody”), usable in experiments on mice retinas involving intravitreally injections (see, e.g., US’502 at ¶¶[0135], [0265], [0289]).
ARVO201926 refers to the Association for Research in Vision and Ophthalmology (ARVO) conference in Canada from April 28 to May 2019, wherein research abstracts were presented (see, e.g., ARVO2019, passim).
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 CNV occurs in “Wet AMD” and other diseases, including ocular histoplasmosis, angioid streaks, pathological myopia, and choroidal ruptures (see, e.g., Spec. filed 11/18/2022 at ¶[0003]).
2 see Spec. filed 11/18/2022 at ¶[0133]; see Reply filed 10/13/2025 at 9.
3 see Spec. filed 11/18/2022 at ¶[0064]; see Reply filed 10/13/2025 at 9.
4 see Spec. filed 11/18/2022 at ¶[0081].
5 see Spec. filed 11/18/2022 at ¶¶[0133], [0135], Figures 15E and 21; see Reply filed 10/13/2025 at 9, noting that no chemical structure or SEQ ID NO was provided for the Anti-VEGF agent, but that the Specification identifies it as AF-493-NA from R&D systems.
6 See Spec. filed 11/18/2022 at ¶¶[0134]-[0135], Figures 15E and 21; see Reply filed 10/13/2025 at 9.
7 AJ315849.1, NCBI.NLM.NIH.GOV, Homo sapiens mRNA for apoA-I binding protein (AIBP gene), NCBI GenBank: AJ315849.1 (PRI 07-OCT-2008), 3 pages also available at https://www.ncbi.nlm.nih.gov/nuccore/AJ315849 (last visited 12/05/2025).
8 NP_658985.2, ncbi.nlm.nih.gov, NAD(P)H-hydrate epimerase precursor [Homo sapiens], NCBI Protein Database Reference Sequence: NP_658985.2 (PRI-28-FEB-2019), 5 pages, also available at https://www.ncbi.nlm.nih.gov/protein/91984773?sat=47&satkey=5072574 (last visited 12/05/2025)
9 Claim 50 in PCT’463.
10 Association for Research in Vision and Ophthalmology (ARVO) conference in Canada from April 28 to May 2019, Schedule-at-a-glance, 1 page (2019).; hereafter “ARVO2019”.
11 Yingbin Fu et al., AIBP suppresses choroidal neovascularization (CNV) by enhancing cholesterol efflux. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3272, attached as 4 pages, also available at https://iovs.arvojournals.org/article.aspx?articleid=2743154 (last visited 12/5/2025); hereafter “Fu”.
12 NP_000030.1, ncbi.nlm.nih.gov, apolipoprotein A-I isoform 1 preproprotein [Homo sapiens], NCBI Protein Database Reference Sequence: NP_000030.1 (PRI 25-FEB-2019), 5 pages, also available at https://www.ncbi.nlm.nih.gov/protein/4557321?sat=47&satkey=5065307 (last visited 12/05/2025)
13 NP_658985.2, ncbi.nlm.nih.gov, NAD(P)H-hydrate epimerase precursor [Homo sapiens], NCBI Protein Database Reference Sequence: NP_658985.2 (PRI-28-FEB-2019), 5 pages, also available at https://www.ncbi.nlm.nih.gov/protein/91984773?sat=47&satkey=5072574 (last visited 12/05/2025)
14 Gallenmore et al., When Anti-VEGF Treatment Fails, Review of Ophthalmology, 20 March 2008, 11 pages, also available at https://www.reviewofophthalmology.com/article/when-anti-vegf-treatment-fails (last visited 5/26/2026).
15 see, e.g., Nystrom v. TREX Co., Inc., 424 F. 3d 1136, 1143 (Fed. Cir. 2005), explaining that "When different words or phrases are used in separate claims, a difference in meaning is presumed).
16 Gallenmore et al., When Anti-VEGF Treatment Fails, Review of Ophthalmology, 20 March 2008, 11 pages, also available at https://www.reviewofophthalmology.com/article/when-anti-vegf-treatment-fails (last visited 5/26/2026).
17 see Spec. filed 11/18/2022 at ¶[0133]; see Reply filed 10/13/2025 at 9.
18 Gallenmore et al., When Anti-VEGF Treatment Fails, Review of Ophthalmology, 20 March 2008, 11 pages, also available at https://www.reviewofophthalmology.com/article/when-anti-vegf-treatment-fails (last visited 5/26/2026).
19 Yingbin Fu et al., AIBP suppresses choroidal neovascularization (CNV) by enhancing cholesterol efflux. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3272, attached as 4 pages, also available at https://iovs.arvojournals.org/article.aspx?articleid=2743154 (last visited 12/5/2025); hereafter “Fu”; cited in previous action.
20 Fu, Oral Presntation - AIBP Suppresses Choroidal Neovascularization (CNV) by Enhancing Cholesterol Efflex”, presented on April 30, 2019, during ARVO Annual Meeting held April 28-May 2, 2019, in Vancouver, Canada; cited in IDS filed 4/29/2026 as Cite No. 2; hereafter “Oral-Presentation”; fee set forth in 37 CFR 1.17(p) was paid.
21 NP_000030.1, ncbi.nlm.nih.gov, apolipoprotein A-I isoform 1 preproprotein [Homo sapiens], NCBI Protein Database Reference Sequence: NP_000030.1 (PRI 25-FEB-2019), 5 pages, also available at https://www.ncbi.nlm.nih.gov/protein/4557321?sat=47&satkey=5065307 (last visited 12/05/2025); cited in previous action.
22 NP_658985.2, ncbi.nlm.nih.gov, NAD(P)H-hydrate epimerase precursor [Homo sapiens], NCBI Protein Database Reference Sequence: NP_658985.2 (PRI-28-FEB-2019), 5 pages, also available at https://www.ncbi.nlm.nih.gov/protein/91984773?sat=47&satkey=5072574 (last visited 12/05/2025); cited in previous action.
23 Per KSR, all that is needed to sustain a determination of obviousness is “A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art” (see, e.g., KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007)); and "[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007) (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273 , 282 , 96 S. Ct. 1532 , 47 L. Ed. 2d 784 (1976)). Here, all components were known in the prior art, the function of each component was known in the prior art, the patient population was known in the prior art, and one of skill in the art could combine such known components, and such combination yields “no more than one would expect from such an arrangement”, namely the successful treatment of CNV in a patient following Anti-VEGF monotherapy failure.
24 see Spec. filed 11/18/2022 at ¶¶[0133], [0135], Figures 15E and 21; see Reply filed 10/13/2025 at 9, noting that no chemical structure or SEQ ID NO was provided for the Anti-VEGF agent, but that the Specification identifies it as AF-493-NA from R&D systems.
25 Per KSR, all that is needed to sustain a determination of obviousness is “A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art” (see, e.g., KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007)); and "[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007) (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273 , 282 , 96 S. Ct. 1532 , 47 L. Ed. 2d 784 (1976)). Here, all components were known in the prior art, the function of each component was known in the prior art, the patient population was known in the prior art, and one of skill in the art could combine such known components, and such combination yields “no more than one would expect from such an arrangement”, namely the successful treatment of CNV in a patient following Anti-VEGF monotherapy failure.
26 Association for Research in Vision and Ophthalmology (ARVO) conference in Canada from April 28 to May 2019, Schedule-at-a-glance, 1 page (2019).; hereafter “ARVO2019”; cited in previous action.
Prosecution Insights