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 1-16, 18, 20, and 31-32 are pending as filed 1/19/2024. Claims 1-14 are withdrawn as directed to a non-elected invention. Claims 15-16, 18, and 31-32 are withdrawn as directed to non-elected species. Claims 20 is presently considered.
Election/Restrictions
Applicant’s election without traverse of Group II (claims 15-16, 18, 20, and 31-32 as filed 1/19/2024, directed to methods of administering a compound in vivo or in vitro) and the species of Figure 3B and Examples 3-5 in the reply filed on 7/08/2026 is acknowledged.
The originally elected species is understood as follows:
The originally elected species was supposed to correspond to a “single Figure or Example”1, but Applicant identified the species of “Figure 3B, also Example 3…also Examples 4-5” (see, e.g., Reply filed 7/08/2026 at 3-5), and therefore a single Figure or example was not clearly identified as required. This is pertinent because Examples 3-5 pertain to different types of macrophages (i.e., RAW 264.7 cells are used at Figure 3(b) and Examples 3-4, but human-derived macrophages at Example 5), and these Examples have different active method steps and compositions. This election is further convoluted by the fact that Figure 3B is illegible:
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Although illegible as filed, instant Figure 3(b) has been reasonably understood to be identical to the subsequently published image Figure 3(b) in Jha et al2:
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Figure of 3(b) is therefore reasonably inferred to show M0 macrophages, specifically Raw 264.7 cells, encapsulated (e.g., “contacted”) with a “PEG-DGEA hydrogel”, wherein the “PEG-DGEA hydrogel” comprises “PEG-PQ-PEG”, “PEG-RGDS”, “PEG-DGEA”, and forms when such components are exposed to Eosin Y and white light (see, e.g., instant Fig. 3(b); see also Jha at Fig. 3(b) on 81; see also Spec. filed 1/19/2024 at Example 3 at 37 at lines 20-22). However, the Reply identifies that the contacted cell is not M0 Raw 264.7 cells, but rather M1 macrophages (see, e.g., Reply filed 7/08/2026 at pages 3-4 at numbers 1 and 3-4). This is only consistent with Figure 3B in view of Example 4, wherein “M0 macrophages were encapsulated in each gel” and “M1 media was added 24 hrs post-encapsulation to stimulate M0 macrophages towards the M1 phenotype” (see, e.g., Spec. filed 1/19/2024 at Figure 4(a), Example 4 at 37 at line 25 to page 38 at line 5), and in view of Example 5, wherein “[f]ollowing encapsulation, human macrophages were stimulated from M0 to M1 phenotype by adding LPS and IFNγ in the RPMI medium” (see, e.g., Spec. filed 1/19/2024 at 38 at lines 19-26). Accordingly, M0 macrophages were initially encapsulated by the “PEG-DGEA hydrogel”, and then stimulated from M0 to the M1 phenotype by adding either “M1 media” or “LPS and IFNγ in the RPMI medium” (see, e.g., Spec. filed 1/19/2024 at Figure 4(a), Example 4 at 37 at line 25 to page 38 at line 5, 38 at lines 19-26), and then the cells were measured for iNOS expression (see, e.g., Spec. filed 1/19/2024 at Examples 4-5 at pages 37 at line 23 to p. 38 at line 31). Accordingly, the originally elected species, consistent with the record and the Reply filed 7/08/2026, is reasonably understood as follows:
The originally elected species is understood to be “a method of inhibiting activation of pro-inflammatory M1 macrophages” as recited at instant claim 20, comprising the steps of (i) encapsulating M0 macrophages with a “PEG-DGEA hydrogel”, (ii) exposing the encapsulated M0 macrophages with “M1 media” to stimulate the macrophages from the M0 to M1 phenotype, which results in the “PEG-DGEA hydrogel” “contacting” M1 macrophages, and (iii) assaying the M1 macrophages for iNOS expression, wherein reduced iNOS expression is indicative of inhibiting activation of pro-inflammatory M1 macrophages
The “PEG-DGEA hydrogel” is understood to be comprised of a 3D crosslinked hydrogel comprising 5 mM PEG-DGEA; 3.5 mM PEG-RGDS (cell adhesive) and 5% PEG-PQ-PEG (enzyme-cleavable), wherein “PQ” is SEQ ID NO: 13 (see, e.g., Reply filed 7/08/2026 at pages 3-4 at numbers 1-2).
The “M1 media” is understood to be RPMI-1640, supplemented with 2 mM L-glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, 0.1 mM sodium pyruvate, 1% non-essential amino acids, 50 µm 2-mercaptoethanol, 10% FBS, 10 ng/ml IFNγ, and 100 ng/ml of LPS (see, e.g., Reply filed 7/08/2026 at page 4 at number 4).
The macrophages are understood to encompass either RAW 264.7 cells (mouse macrophage cell line) or human macrophages (see, e.g., Reply filed 7/08/2026 at page 3-4 at number 3).
The originally elected species is understood to read upon only instant claim 20 (see, e.g., Reply filed 7/08/2026 at page 4 at number 5), at least because claims 15-16, 18, and 31-32 of Group II require in vivo treatment of a subject.
Following extensive search and examination, the originally elected species has been deemed free of the prior art. The point of novelty is the combination of the specific limitations of the unclaimed M1 media, the unclaimed M0 to M1 stimulation step, followed by the unclaimed step of assaying iNOS expression. Per MPEP § 803.02(III)
If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended. If prior art is then found that anticipates or renders obvious the Markush claim with respect to a nonelected species, the Markush claim shall be rejected; claims to the nonelected species would still be held withdrawn from further consideration. The prior art search will not be extended unnecessarily to cover all nonelected species.
Accordingly, Examination was extended to a non-elected species of a method of contacting a hydrogel of WO’049 with a tumor-associated macrophage. Following extensive search and examination, the non-elected species was deemed obvious in view of the prior art as applied below. Per MPEP § 803.02(III), claims directed to other nonelected species have been withdrawn.
Claims 1-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/08/2026.
Claims 15-16, 18, and 31-32 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 7/08/2026.
Claim 20 is presently considered.
Priority
The priority claim to US Provisional 63/225177, filed 7/23/2021, is acknowledged.
Information Disclosure Statement
The IDS filed 8/16/2024 is acknowledged and presently considered.
Applicant is advised that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because Figures 1(a), 2(a)-2(b), 3(a)-(c), 4(a)-(b), and 5(a) contain one or more instances of illegible text. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
Sequence Listing: The instant disclosure is objected to for not complying with 37 C.F.R. 1.821 as detailed in MPEP §§ 2421–2424. Specifically, the instant application does not comply with 37 C.F.R. 1.821(b)-(e). The instant claims and/or disclosure contain references or disclosures of amino acid sequences that should be accompanied by a sequence listing and identified using "SEQ ID NOs” as prescribed (see, MPEP §§ 2421–2424). Specifically, the instant application discloses sequences at least at Figures 5(a)-(b), 6-10, 12, page 2 at lines 20-30, page 36 at lines 31-34, page 37 at lines 15-31, page 39, page 41 at lines 4-15, pages 41-42 at Table 1, page 42 at lines 1-32, page 43 at lines 4-10, page 44 at lines 17-28, passim. This list is not exhaustive as the issue is pervasive.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Appropriate correction is required.
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).
Claim 20 is representative of the pending claim scope and presently recites:
20. (Currently Amended) A method of inhibiting activation of pro-inflammatory M1 macrophages, comprising contacting one or more macrophages with a composition comprising DGEA, wherein said composition comprising DGEA is a hydrogel composition comprising DGEA and one or more synthetic polymers, wherein said hydrogel composition comprising DGEA and one or more synthetic polymers is the crosslinked poly(alkylene glycol)-based hydrogel composition of claim 1.
Accordingly, the pending claim scope is limited to methods of “inhibiting activation of pro-inflammatory M1 macrophages”, which comprise at least the step of “contacting one or more macrophages” with a composition of claim 1.
Regarding the preamble of claim 20 (“of inhibiting activation of pro-inflammatory M1 macrophages”), per MPEP § 2111.02, “where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation”. Here, the body of claim 20 is understood to recite a structurally complete invention, and therefore the preamble is deemed fully satisfied by prior art that satisfies the steps and structures recited in the body of the claim (see also MPEP § 2111.04(I), noting that “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”).
“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)).
“Contacting” is undefined on record, and is therefore given the broadest interpretation consistent with the disclosure and examples of record. The term is understood to include any transient, physical contact, regardless of duration.
“One or more macrophages” is understood to read upon any type of macrophage including M0, M1, or M2 macrophages; this is reasonable because “one or more macrophages” is not the same as “M1 macrophages” as recited in the preamble (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"), and the Specification explicitly notes the existence of multiple types of macrophages (see, e.g., Spec. filed 1/19/2024 at 27 at lines 1-26, noting that the Specification even explains that the “one or more macrophages to be contacted” may be unactivated (M0 macrophages)”). Accordingly, the method broadly encompasses “contacting” any type of macrophage and is not limited to M1 macrophages per limitations set forth in the body of claim 20.
The hydrogel “composition . . . of claim 1” is understood to incorporate a composition of claim 1, wherein claim 1 recites:
1. (Original) A crosslinked poly(alkylene glycol)-based hydrogel composition, comprising:
a cell adhesive peptide covalently conjugated with a first poly(alkylene glycol);
a cleavable peptide linker covalently conjugated with a second and third poly(alkylene glycol); and
DGEA (SEQ ID NO: 12) covalently conjugated with a fourth poly(alkylene glycol);
wherein, said first, second, third, and fourth poly(alkylene glycol), in each instance, are the same or different.
A “cell adhesive peptide” is understood to include any art-recognized “cell adhesive peptide”, including those enumerated in the specification (see, e.g., Spec. filed 1/19/2024 at 10 at lines 23-28, referring to instant SEQ ID NOs: 4-11 and 13 as “cell adhesive peptides”). A “cleavable peptide linker” is understood to include any art-recognized “cleavable peptide”, including those enumerated in the specification (see, e.g., Spec. filed 1/19/2024 at 11 at lines 9-15, referring to instant SEQ ID NOs: 1-3). A “poly(alkylene glycol)” is understood to be modified or unmodified poly(alkylene glycols), including those enumerated in the specification (see, e.g., Spec. filed 1/19/2024 at 12 at lines 6 to page 13 at line 28, exemplifying PEG, acrylate-PEG, PEG-NHS, PEG-SVA, PEG-MAL, among multiple others). Accordingly, at claim 1 in view of the phrase “comprising” and “-based hydrogel”, it is reasonably inferred that the hydrogel of claim 1 incorporated by claim 20 may include additional components and modifications to the poly(alkylene glycol) portions, so long as the components are crosslinked.
Additional claim interpretations are discussed below.
Claim Objection
Claim 20 is objected to because of the following informalities:
Claim 20 is objected to because it contains redundant and superfluous language that fails to meaningfully limit the pending claim scope. Specifically, the following proposed amendment removes over 30 unnecessary words without altering the scope of the claim:
20. (Currently Amended) A method of inhibiting activation of pro-inflammatory M1 macrophages, comprising contacting one or more macrophages with a composition
Redundant and superfluous language should be removed to enhance claim clarity and to minimize potential confusion.
Sequence Listing: Claim 20 is objected to for not complying with 37 C.F.R. 1.821 as detailed in MPEP §§ 2421–2424. Specifically, the instant application does not comply with 37 C.F.R. 1.821(b)-(e). The instant claim contains references or disclosures of amino acid sequences (e.g., “DGEA”) that should be accompanied by a sequence listing and identified using "SEQ ID NOs” as prescribed (see, MPEP §§ 2421–2424).
Appropriate correction is required.
Claim Rejections
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.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 20 recites and refers to a “composition … of claim 1”, but such compositions include functionally defined components, including “a cell adhesive peptide” (see, e.g., instant claims 1 and 20), which renders the metes and bounds of claim 20 ambiguous. More specifically, the term “cell adhesive peptide” is not specifically defined using a structure/function relationship or identifying a commonly shared and required structural motif, but rather the term is defined functionally (see, e.g., Spec. filed 1/19/2024 at 10 at lines 21-22, defining a “cell adhesive peptide” tautologically as “a peptide that promotes cell adhesion”, with no structure/function relationship). Accordingly, the genus of “cell adhesive peptides” may encompass trillions of sequences, or perhaps less than twenty sequences. At best, the term is exemplified by reference to SEQ ID NOs: 4-11 and 13 (see, e.g., Spec. filed 1/19/2024 at 10 at lines 21-29, p. 29 at lines 17-23), but these sequences share no common structure or consensus sequence. No clear structure/function relationship is taught in the prior art. 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 reference at claim 20 merely amounts to a description of functions or results to be achieved by the administered compound 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 peptide sequences do or do not infringe upon the scope of claim 20 (or claim 1). Accordingly, the metes and bounds of claim 20 are indefinite due to the usage of ill-defined, but variable and functionally defined compositions comprising “a cell adhesive peptide”. For purposes of applying prior art, the “cell adhesive peptide” component is deemed fully satisfied by instant SEQ ID NOs: 4-11, 13, and any prior art sequence of record that is explicitly taught and identified as a “cell adhesive peptide”.
Claim 20 recites and refers to a “composition … of claim 1”:
20. (Currently Amended) A method of inhibiting activation of pro-inflammatory M1 macrophages, comprising contacting one or more macrophages with a composition comprising DGEA, wherein said composition comprising DGEA is a hydrogel composition comprising DGEA and one or more synthetic polymers, wherein said hydrogel composition comprising DGEA and one or more synthetic polymers is the crosslinked poly(alkylene glycol)-based hydrogel composition of claim 1.
Wherein claim 20 incorporates the limitations of claim 1, which recites:
1. (Original) A crosslinked poly(alkylene glycol)-based hydrogel composition, comprising:
a cell adhesive peptide covalently conjugated with a first poly(alkylene glycol);
a cleavable peptide linker covalently conjugated with a second and third poly(alkylene glycol); and
DGEA (SEQ ID NO: 12) covalently conjugated with a fourth poly(alkylene glycol);
wherein, said first, second, third, and fourth poly(alkylene glycol), in each instance, are the same or different.
Therefore, claims 1 and 20 only ostensibly recite and require three distinct components:
(i) DGEA conjugated to a PAG4;
(ii) a “cell adhesive peptide” conjugated to a PAG; and
(iii) a “cleavable peptide linker” linked to two PAGs (e.g., Peptide-PAG-PAG, PAG-PAG-Peptide, or PAG-Peptide-PAG).
The following facts challenge the interpretation that the claim requires three distinct components:
First, WO2019/113026A1 discloses that DGEA is an art-recognized “cell-adhesive peptide” (see, e.g., WO’026 at 3 at lines 10-17, p. 11 at lines 33-37), and is disclosed as equivalent to RGDS, RDGS, RGES, REGS, IKVAV, VVIAK, YIGSR, YSRIG, and DAEG (see id.), which each prior art sequences corresponds to instant SEQ ID NOs: 4-11 and 13 (compare id. with instant SEQ ID NOs: 4-11 and 13, noting that the numbering is identical in WO’026 and the instant cases). Therefore, DGEA is a “cell-adhesive peptide”.
Second, the arrangements of “Peptide-PAG-PAG” and “PAG-PAG-Peptide” for the third component are arbitrary, because, for example, a PEG10 could be viewed as a single PAG or arbitrarily as two PAG units (e.g., PEG5-PEG5, PEG2-PEG8, etc.).
Third, all peptides are cleavable chemically, enzymatically, or via bond ionization by high energy X-rays. Therefore, DGEA is a “cleavable” peptide and can link two components upon crosslinking; according, DGEA is a “cleavable peptide linker”.
Fourth, claim 1 explicitly identifies that the “first, second, third, and fourth poly(alkylene glycol), in each instance” may be “the same” or different (see instant claim 1.) Therefore, the first and fourth PAG may be identical (e.g., PEG10) and the second and third PAG may be identical and in combination yield the first and fourth PAG (e.g., PEG5-PEG5).
In view of these facts, it is noted that the three components could each be fully satisfied by a single peptide macromer of DGEA-PEG10 (or another DGEA-PAG molecule), since DGEA is also a cleavable peptide and is also an art-recognized cell-adhesive peptide. Accordingly, because DGEA-PAG can perform all three required roles in the composition, it is unclear if the claim scope requires three separate and distinct “peptides” or if all recited peptide components may be “DGEA”. Although there is a general presumption that separately listed components require separate and distinct structures5, this is not a per se rule, and in the instant case the peptide component is not claimed in isolation but in combination with a PAG; for example, DGEA-(PEG-NHS), DGEA-(PEG-SVA), and DGEA-(PEG5-PEG-SS) are obvious variants but are three chemically distinct structures sharing the same peptide but differing by the functional moiety of the PEG group. Therefore, because obvious variants of the same basic structure exist (e.g., DGEA-PAG variants) and each variant is ostensibly chemically distinct, then each variant could presumably satisfy each peptide roll presently claimed. Therefore, it is presently unclear if DGEA satisfies all required peptide-related limitations, or if the separate descriptions are intended to preclude such species, or otherwise limit “cleavable” to peptide sequences cleavable by a specific enzyme. Accordingly, there is a material and substantial concern regarding what compounds do or do not satisfy the structural requirements of instant claim 20, and therefore claim 20 is rejected as indefinite.
Accordingly, claim 20 is rejected as indefinite.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over WO2019/113026 A1 (June 13, 2019) in view of Nielsen et al.6 and Cha et al7.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
WO’026 pertains to methods of screening anti-cancer drugs on a model system comprising cancer cells in contact with a crosslinked poly(alkylene glycol)(“PAG”)-based hydrogel compositions (see, e.g., WO’026 at title, abs). Regarding instant claim 20 and a hydrogel “composition . . . of claim 1”: WO’026 teaches and discloses crosslinked poly(alkylene glycol)(“PAG”)-based hydrogel compositions (see, e.g., WO’026 at title, abs), and methods of using such crosslinked hydrogel compositions in “screening an agent for effectiveness of the agent against cancer cells” (see id; see also id. at 4-5 at bridging ¶, 47-48 at Example 11, Figure 4). Regarding instant claim 20 and a “composition …. of claim 1” comprising the peptides of DGEA and RGDS, WO’026 identifies that the crosslinked PAG-based hydrogel compositions may comprise polymer-peptide macromers, including cell-adhesive macromers comprising a PAG “covalently conjugated with a cell-adhesive peptide” such as RGDS and DGEA (see, e.g., WO’026 at 3 at lines 4-19, SEQ ID NOs: 4-13, noting that SEQ ID NO: 12 is DGEA, and SEQ ID NO: 4 is RGDS). Regarding the selection of two, three or more cell-adhesive peptides, the structure, effect, and mechanism of cell-adhesive peptides are unambiguously disclosed by WO’026, and variants of such crosslinked PAG-based hydrogel compositions comprising mixtures of two or more cell-adhesive peptides would be predicted and expected to provide the same functionality as a single cell-adhesive peptide (see, e.g., MPEP §§ 2144.06(I)-(II), 2144.07). Regarding instant claim 20 and a “composition …. of claim 1” comprising the peptides of DGEA and RGDS conjugated to a poly(alkylene glycol), WO’026 identifies that the crosslinked PAG-based hydrogel compositions may comprise polymer-peptide macromers, including cell-adhesive macromers comprising a PAG “covalently conjugated with a cell-adhesive peptide” such as RGDS and DGEA (see, e.g., WO’026 at 3 at lines 4-19, SEQ ID NOs: 4-13), and exemplifies the “cell-adhesive macromer” of “PEG-RGDS” (see, e.g., WO’026 at 5 at lines 30-35). Accordingly, an artisan would readily appreciate that any and all of the disclosed “cell-adhesive peptides” (see, e.g., WO’026 at 3 at lines 4-19, SEQ ID NOs: 4-13) could be conjugated to a poly(alkylene glycol) such as PEG or other suitable poly(alkylene glycol) (see, e.g., WO’026 at 11 at lines 6-37, disclosing PEG-SVA, PEG-NHS, PEG-MAL-etc., etc.), with the explicit understanding that each poly(alkylene glycol) could be “the same” or “different” (see id. at 11 at lines 25-30). Regarding claim 20 and a “composition …. of claim 1” comprising a cleavable peptide linker covalently conjugated with two poly(alkylene glycol) moieties, WO’026 identifies that the crosslinked hydrogel compositions could comprise “the matrix metalloproteinase cleavable peptide sequence, GGGPQGIWGQGK” (“PQ”) to form a PEG-PQ-PEG macromer “consisting of the PQ sequence flanked by two PEG chains” (see, e.g., WO’026 at 6 at lines 10-16; see also, id. at 10 at lines 24-33). Accordingly, WO’026 teaches and directs artisans to make any use crosslinked hydrogel compositions comprising PEG-PQ-PEG. Regarding instant claim 20 and methods of contacting a “composition …. of claim 1” to cells, WO’026 teaches and discloses methods of using crosslinked hydrogel compositions in “screening an agent for effectiveness of the agent against cancer cells” (see id; see also id. at 4-5 at bridging ¶, 47-48 at Example 11, Figure 4, claims 1(i), and claim 24). In summary, the composition utilized in the claimed method and “contacted” to cells, was known and disclosed in the prior art for use in screening methods that necessarily involved “contacting” the composition to cells.
The prior art of WO’026 differs from the instant claim scope as follows: WO’026 teaches and discloses methods wherein the cells utilized are “cancer cells” rather than “one or more macrophages” as required by instant claim 20. Therefore, the issue is whether or not it would be obvious to utilize such cancer screening methods with macrophages as instantly claimed.
WO’026 directs artisans to in vitro models for recapitulating disseminated tumor cells (DTCs) fates and tumor microenvironments in order to model DTC shifts from dormancy to an aggressive and invasive growth state: WO’026 pertains to methods of screening anti-cancer drugs on a model system comprising cancer cells in contact with a crosslinked poly(alkylene glycol)(“PAG”)-based hydrogel compositions (see, e.g., WO’026 at title, abs, Fig. 3-4), wherein the in vitro model systems are specifically intended recapitulate tumor microenvironments and to facilitate identification screening methods for treatments of disseminated tumor cells (DTCs) (see, e.g., WO’026 at title, abs, 1 at line 11 to page 2 at line 22, p. 1 at lines 25-32, p. 2 at lines 25-28), wherein the identified purpose is to develop “in vitro models that can recapitulate specific fates of DTCs, facilitate further investigation of underlying biological mechanisms necessary for understanding tumor dormancy, and for use in pre-clinical information for future drug development” (see, e.g., WO’026 at 2 at lines 19-22), including triggers from dormancy toward aggressive and invasive growth (see id. at 2 at lines 1-22; see also WO’026 at 8 at lines 10-21, 10 at lines 19-23, noting that “cancer” includes patient-derived cancer cells and patient derived xenografts). More specifically, WO’026 teaches and discloses in vitro model systems intended to represent “four systems” that represent different “states of the cancer cells” (see, e.g., WO’026 at 2 at lines 19-22, Fig. 3-4), including “invasive growth” (see, e.g., WO’026 at Fig. 4, esp. at Fig. 4 at Route 3, p. 1 at lines 25-32, p. 2 at lines 25-28). Accordingly, an artisan would readily appreciate that the disclosed in vitro models were intended to recapitulate the tumor microenvironments and fates of disseminated tumor cells (DTCs), included microenvironmental factors contributing to reactivating dormant cells toward invasive growth (see, e.g., WO’026 at Fig. 4, esp. at Fig. 4 at Route 3, claims 1, 24-25, 27).
Macrophages promote disseminated tumor cell (DTC) survival, extravasation, and growth: Nielsen identifies that “macrophages are one of the most abundant immune cells in the tumour microenvironment”, and that macrophages promote the “extravasation and survival” of disseminated tumour cells, “inhibit[] immune-mediated clearance” of DTCs, and that macrophages “promote the growth of disseminated tumour cells” (see, e.g., Nielsen at title, abs, Fig. 1 on 5), and promote chemoresistance (see, e.g., Nielsen at 4 at §§ 4, Fig. 1 on 5). Accordingly, macrophages are a well-known component of tumor microenvironments and are a well-known factor determining factor in the fate of disseminated tumor cells (DTCs).
Including macrophages in the in vitro model of WO’026 would predictably result in an improved in vitro model system that better represented tumor microenvironments of disseminated tumor cells: As noted above, macrophages are naturally abundant in tumor microenvironments and directly alter the “fate” of disseminated tumor cells (see, e.g., Nielsen at title, abs, Fig. 1 on 5, 4 at §§ 4, Fig. 1 on 5). Therefore, an artisan would readily appreciate that including macrophages in the in vitro model system and screens disclosed by WO’026 (see, e.g., WO’026 at claims 1, 24-27, and 29), the system would better represent DTC tumor microenvironments, which would predictably permit artisans to utilize the in vitro system and screening methods of WO’026 to identify potent anticancer drugs. Furthermore, such modification is consistent with the suggestions and guidance of Nielsen, which states that the “development of agents inhibiting the recruitment or the protumorigenic effector functions of macrophages in both the primary tumour and at the metastatic site is a promising strategy to improve cancer survival in the future” (see, e.g., Nielsen at title, abs).
An artisan modifying the WO’026 in vitro model of disseminated tumor cells (DTCs) and screening methods would readily appreciate that adhesive peptide selection would impact macrophages in a predictable manner: As explained by Nielsen, different types and subtypes of macrophages exist (see, e.g., Nielsen, passim). However, Nielsen identifies that TAMs (Tumour-Associated Macrophages) are “typically associated with an M2-like polarization state” (see, e.g., Nielsen at 2-3 at bridging ¶). This is pertinent because an artisan would appreciate that the specific selection of specific cell adhesive peptides disclosed by WO’026 (see, e.g., WO’026 at 3 at lines 9-18) would impact the tumor microenvironment; specifically, Cha discloses that macrophages can be influenced to express higher levels of M2 macrophage markers by exposing the macrophages to the peptide of DGEA (see, e.g., Cha at title, abs, page 8 at col II at 1st full ¶, noting that “these data indicate that simple DGEA motives … induced a partial shift of human primary monocytes toward the M2 macrophage phenotype and created a cytokine environment that promoted M2 macrophages polarization”). Accordingly, the inclusion of macrophages in the WO’026 in vitro model would require assessment of art-recognized relationships between the specific cell adhesive peptides disclosed by WO’026, and macrophage biology. Here, an artisan would appreciate that utilizing DGEA as taught by WO’026, in the presence of a macrophage, would be expected to cause the macrophage to adopt an M2 macrophage phenotype. Therefore, the usage of DGEA would be desirable in an in vitro DTC model system as taught by WO’026, because TAMs (Tumour-Associated Macrophages) are “typically associated with an M2-like polarization state” (see, e.g., Nielsen at 2-3 at bridging ¶), and therefore the usage of DGEA and inclusion of macrophages would predictably replicate the environment of Tumor-associated macrophages.
In summary, WO’026 discloses an in vitro model system for modeling the fates of disseminated tumor cells (DTCs) (e.g., dormancy, survival , aggressive growth, etc.); and Nielsen teaches that DTCs are linked to tumor-associated macrophages (TAMs). Therefore, an artisan would reasonably modify the WO’026 in vitro model to include macrophages to better model and represent DTC tumor microenvironments, wherein the usage of the specific cell adhesive peptide of DGEA as taught by the primary and tertiary references, would predictably model an M2 macrophage polarization state, thereby permitting the in vitro model system to better represent the environment pertinent to DTCs and TAMs. Such a model system would permit screening of anticancer agents exactly as taught and suggested by the primary and secondary references.
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 claimed invention is the obvious application of a known prior art element (e.g., macrophages and Tumor-associated macrophages (TAMs)) to improve the known in vitro model system of DTCs and associated drug screening methods of the primary reference, in a predictable manner, namely wherein the inclusion of macrophages and TAMs would improve the model system by better representing in vivo tumor microenvironments, thereby permitting the in vitro model system of DTCs and associated drug screening methods of the primary reference to more accurately identify promising drugs for the treatment of DTCs in vivo (see, e.g., MPEP § 2143(I)(A), (C), (D), (F), and (G)).
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. As explained above, the selection of the prior art adhesive peptide DGEA would predictably result in a TAM and M2-macrophage tumor microenvironment (which would result in reducing M1 phenotypes concomitantly). Such result is neither surprising or unexpected, because it is merely the expected result in view of the prior art.
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 improve a known in vitro model system and screening method taught in the prior art, by making a known alteration that results in the in vitro model system better representing the relevant in vivo model system.
Accordingly, claim 20 is rejected as obvious in view of the prior art.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Belgiovine et al.8 discusses anti-cancer therapies based upon targeting tumor-associated macrophages (TAMs) (see, e.g., Belgiovine at title, abs, passim). At the abstract, Belgiovine notes that
…tumor-associated macrophages (TAMs) are the most abundant leucocyte subset in many cancers and play a major role in the creation of a protective niche for tumor cells. Their ability to generate an immune-suppressive environment is crucial to escape the immune system and to allow the tumor to proliferate and metastasize to distant sites. Conventional therapies, including chemotherapy and radiotherapy, are often not able to limit cancer growth due to the presence of pro-tumoral TAMs; these are also responsible for the failure of novel immunotherapies based on immune-checkpoint inhibition. Several novel therapeutic strategies have been implemented to deplete TAMs; however, more recent approaches aim to use TAMs themselves as weapons to fight cancer. Exploiting their functional plasticity, the reprogramming of TAMs aims to convert immunosuppressive and pro-tumoral macrophages into immunostimulatory and anti-tumor cytotoxic effector cells. This shift eventually leads to the reconstitution of a reactive immune landscape able to destroy the tumor. In this review, we summarize the current knowledge on strategies able to reprogram TAMs with single as well as combination therapies
(see id. at abs; see also id. at Fig. 1 on 3). Accordingly, TAMs are recognized as a part of cancer survival, growth, and treatment strategies.
Dandekar et al9 pertains to tumor-associated macrophages (TAMs) and the roles of macrophages in malignancies (see, e.g., Dandekar at title, abs, Fig. 1 on 151, passim).
US20210008092 pertains to a method of treating a disease or disorder associated with excessive or sustained inflammation in a subject by decreasing M1 macrophages (see, e.g., US’092 at title, abs, ¶¶[0019]-[0023], [0123]).
Conclusion
No claims are allowed.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 See Requirement mailed 6/04/2025 at 5 at 1st bullet.
2 Jha et al., Collagen-derived peptide, DGEA, inhibits pro-inflammatory macrophages in biofunctional hydrogels. J Mater Res. 2022;37(1):77-87. doi: 10.1557/s43578-021-00423-y. Epub 2021 Dec 2. PMID: 35185277; PMCID: PMC8810474; at Fig. 3(b) on page 81.
3 SEQ ID NO: 1 is GGGPQGIWGQGK
4 “PAG” refers to any poly(alkylene glycol)
5 See, e.g., Becton, Dickinson & Co. v. Tyco Healthcare Group, LP, Nos. 09-1053, -1111 (Fed. Cir. July 29, 2010); see also Gaus v. Conair Corp., 363 F.3d 1284, 1288 (Fed. Cir. 2004); Magnolia Medical Technologies, Inc. v. Kurin, Inc., Case No. 24-2001 (Fed. Cir. Mar. 6, 2026).
6 Nielsen et al., Macrophages as Key Drivers of Cancer Progression and Metastasis. Mediators Inflamm. 2017;2017:9624760. doi: 10.1155/2017/9624760. Epub 2017 Jan 22. PMID: 28210073; PMCID: PMC5292164.
7 Cha et al., Integrin-Mediated Interactions Control Macrophage Polarization in 3D Hydrogels. Adv Healthc Mater. 2017 Nov;6(21):10.1002/adhm.201700289. doi: 10.1002/adhm.201700289. Epub 2017 Aug 7. PMID: 28782184; PMCID: PMC5677560.
8 Belgiovine et al., Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing. J Clin Med. 2020 Oct 8;9(10):3226. doi: 10.3390/jcm9103226. PMID: 33050070; PMCID: PMC7600332.
9 Dandekar et al., Role of macrophages in malignancy. Ann Maxillofac Surg. 2011 Jul;1(2):150-4. doi: 10.4103/2231-0746.92782. PMID: 23482819; PMCID: PMC3591014.
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