App. No. 19/650,706

the composition 'in the form of a liposome' with the GO-HA conjugate carrier (as the OA maps the combined composition)

For counsel to weigh: Holsworth's central mechanism is that the covalently-linked GO-HA conjugate is itself the carrier/matrix that solubilizes and disperses the poorly water-soluble XAV939 — Holsworth states 'the GO and HA are covalently linked to form a matrix component (or a carrier), which can serve to solubilize XAV939' (Holsworth [0025]), yielding a 'viscous suspension' in which 'XAV939 is evenly dispersed... stable at room temperature for months' (Holsworth [0029]). Recasting that GO-HA suspension into a phosphatidylcholine liposome vesicle proposes a fundamentally different solubilization/delivery mechanism, which would change how Holsworth's composition functions rather than merely add an ingredient. Under MPEP § 2143.01 a proposed modification cannot change the principle of operation of the reference being modified, and the OA does not explain how the GO-HA graphene-oxide sheet conjugate is accommodated within, or compatible with, a phospholipid bilayer vesicle. This rests entirely on fully-grounded Holsworth text.

• —Holsworth [0025]: 'the GO and HA are covalently linked to form a matrix component (or a carrier), which can serve to solubilize XAV939 as well as providing other simultaneous benefits to wound healing'
• —Holsworth [0029]: 'XAV939 is evenly dispersed in the viscous suspension, which is stable at room temperature for months'
• —Holsworth abstract/claim 1: composition is GO-HA + XAV939 + water, optionally PEG surfactant — no liposome

Risk The examiner may reply that adding a liposomal carrier does not disable Holsworth's GO-HA and that combining two known solubilizing strategies is permissible. Prosecution-history caution: characterizing GO-HA as the sole/essential solubilizing mechanism could narrow later claim scope in the file wrapper — frame the point as directed to the combination's rationale, not as a disavowal of GO-HA-plus-carrier embodiments.

the overall combined composition (liposome form with the recited excipients)

For counsel to weigh: the OA's motivation statements repeatedly reduce to the conclusion that liposomes and the named excipients are 'suitable,' citing MPEP 2144.07 (e.g., 'liposome is a suitable formulation for XAV939' and phosphatidylcholine/butylene glycol/ethanol are 'suitable ingredients'). Under MPEP § 2143.01 the reasoning to combine must be articulated with a rational underpinning tied to factual findings, and a bare assertion that a combination 'would have been obvious' or that ingredients are 'suitable' is legally insufficient. The OA does not articulate why a PHOSITA would have moved from Holsworth's GO-HA aqueous suspension to a liposome, beyond the conclusory suitability label. This attack rests on the OA's own text and the fully-grounded references.

• —OA §103: 'liposome is a suitable formulation for XAV939 as suggested by Boasberg et al. and Young. MPEP 2144.07'
• —OA §103: phosphatidylcholine, butylene glycol and ethanol are 'suitable ingredients in the topical composition comprising XAV939. MPEP 2144.07'

Risk The examiner can cure a conclusory-rationale objection by supplying additional articulated reasoning on the record rather than withdrawing the rejection, so this argument is best paired with the substantive combination attacks (ranks 1-4) rather than stood alone.

the composition combining the GO-HA conjugate and XAV939 'in the form of a liposome'

For counsel to weigh: the OA supplies no factual finding that a PHOSITA would have reasonably expected a covalently-linked graphene-oxide/hyaluronic-acid conjugate — a rigid, planar, several-hundred-nanometer-to-micrometer sheet material (Holsworth, description: GO is 'several hundreds of nanometers, up to several micrometers, its planar direction, and about 0.7-1.2 nm in thickness') — to be stably incorporated into a phosphatidylcholine liposome vesicle while retaining XAV939 solubilization. Obviousness requires a reasonable expectation of success grounded in the references' actual teachings (MPEP § 2143.02), and formulation of hydrophobic small molecules with novel carriers is an area of recognized unpredictability. The OA's support is the bare assertion that 'liposome is a suitable formulation for XAV939' (citing MPEP 2144.07), which states a conclusion rather than the factual predicate for expected success. Both anchor references are fully grounded.

• —Holsworth description: GO 'can have several hundreds of nanometers, up to several micrometers, its planar direction, and about 0.7-1.2 nm in thickness'
• —OA §103: 'One of ordinary skill... would have been motivated to prepare composition comprising XAV939 and GO-HA in the liposome formulation because liposome is a suitable formulation for XAV939... MPEP 2144.07'
• —Boasberg Background characterizes liposomes generically ('composed primarily of phospholipids such as phosphatidylcholine...') without addressing graphene-oxide-conjugate compatibility

Risk The examiner may point to MPEP 2144.07 (suitability of art-recognized formulations) and argue absolute predictability is not required. Counsel may need a § 1.132 declaration addressing whether GO-HA is physically compatible with liposome formation to convert this from attorney argument into evidence.

the composition in the form of a liposome comprising phosphatidylcholine, ethanol (and the phospholipid vesicle carrier) as recited in claims 61-65/72 (claim text 61-79 not in the provided claims document; hooks taken from the OA's description)

For counsel to weigh: the examiner draws phosphatidylcholine liposomes and ethanol from Boasberg, but in the Boasberg text before us those items appear in the BACKGROUND section as a survey of conventional carrier systems, immediately followed by Boasberg's own statement that these known systems are deficient — 'Despite the wide range of conventional delivery systems known in the art, there is still a need for an improved delivery system' (Boasberg, Background). Boasberg's actual invention is a three-part 'targeting composition' built around a collagen-binding targeting moiety (Boasberg, abstract and claim 1), not a liposome. A reference must be read in its entirety (MPEP § 2141.02), and reliance on a passage the reference characterizes as inadequate undercuts, rather than supplies, a motivation to reformulate Holsworth as a liposome. This is a fully-grounded mischaracterization: the disparaging background language is in the retrieved Boasberg text.

• —Boasberg Background: 'Liposomes are composed primarily of phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and α-L-dipalmitoyl-phosphatidylcholine...'
• —Boasberg Background: 'Despite the wide range of conventional delivery systems known in the art, there is still a need for an improved delivery system for use in delivering a broad range of active ingredients to the skin...'
• —Boasberg claim 1 and abstract: the invention is a 'targeting composition' comprising a skin care/cosmeceutical agent, an intermediate release linker, and 'a targeting moiety... for binding the targeting composition to native collagen fibers'

Risk The examiner will respond that background disclosure is still prior-art disclosure available for what it teaches and that Boasberg need not prefer liposomes to make them known. Counsel should confirm whether the OA's specific paragraph cites ([0165-0166], [0242], [0412-0413]) contain affirmative (non-background) teaching before over-relying on the 'disparaged background' framing.

the particular combination of phosphatidylcholine + butylene glycol + ethanol + polysorbate 20 in liposome form, together with XAV939

For counsel to weigh: in the Boasberg text before us the skin care agent is named only generically as one of 'retinoids, hydroxyacids, esters of hydroxyacids, skin treatment products, and Wnt pathway modulators' (Boasberg summary/claim 83), and butylene glycol appears buried within a very large alkanediol/cosmeceutical enumeration. The examiner assembles exactly phosphatidylcholine, butylene glycol, ethanol, and polysorbate 20 and pairs them with XAV939 and Holsworth's GO-HA; the specific selection of these particular items from Boasberg's sprawling, non-exhaustive lists appears to be guided by the applicant's own disclosure rather than by any teaching in Boasberg directing that combination (MPEP § 2143.01 forbids hindsight drawn only from the applicant's disclosure). The OA's stated rationale is the conclusory statement that these are 'suitable ingredients' (MPEP 2144.07), which does not identify why a PHOSITA would pick this particular set.

• —Boasberg summary/claim 83: skin care agent 'selected from the group consisting of retinoids, hydroxyacids, esters of hydroxyacids, skin treatment products, and Wnt pathway modulators' (XAV939 not named in the provided text)
• —Boasberg lists butylene glycol only within 'an alkanediol selected from the group consisting of 1,2-propanediol, butyleneglycol, 2-ethyl-1,3-hexanediol, and 2-methyl-2,4-pentanediol' and within an extensive cosmeceutical enumeration
• —OA §103: motivation stated as ingredients being 'suitable ingredients in the topical composition comprising XAV939. MPEP 2144.07'

Risk The examiner may respond that picking known excipients from a list of art-recognized options is within ordinary skill (MPEP 2144.07) and that Wnt modulators encompass XAV939. Counsel should verify whether the OA's cites (Boasberg [0165-0166] naming XAV939, [0412-0413] naming polysorbate 20) contain express naming in the full text before asserting Boasberg names only a genus, since those paragraphs are outside the retrieved excerpt.

topical liposome/lipid administration of XAV939 (the OA cites Young pages 16-17 for this)

For counsel to weigh: Young is relied on for topical delivery of XAV939 'via lipid composition such as liposome' (OA, citing Young pages 16, lines 5-10 and page 17), but Young's claims as retrieved recite administration only 'systemically' (claim 3) or 'local or regional to an OA disease site' (claim 4) — not topical liposome. The specification pages the examiner cites for the lipid/liposome teaching are not part of the text available for review, so the specific teaching the OA leans on cannot be confirmed here. Because Young's claim text is grounded but the cited description pages are not, counsel should obtain and verify Young pages 16-17 before treating Young as supplying a topical-liposome teaching for XAV939. Absent that verification, Young's contribution on the available record is limited to identifying XAV939 as a Wnt/β-catenin inhibitor (Young claim 6).

• —Young claim 3: 'wherein said inhibitor is administered systemically'; claim 4: 'administered local or regional to an OA disease site'
• —Young claim 6 identifies XAV-939 as the inhibitor
• —OA2 reality check: 'The specification pages the examiner cites for topical, lipid, and liposome teachings (pages 16-17) are NOT part of the available text; only the abstract and claims are before this reviewer'

Risk Because Young pages 16-17 were not retrieved, this is a verify-first posture, not a proven mischaracterization — it must not be relied on as dispositive. The examiner may quote the actual page 16-17 text in reply; counsel should pull the full Young document first.

the surfactant being polysorbate 20 (in place of Holsworth's PEG)

For counsel to weigh: the OA treats replacing Holsworth's PEG surfactant with polysorbate 20 as a simple substitution of one known equivalent for another under MPEP § 2143(B). A simple-substitution rationale requires a factual showing that the substituted element was recognized as functionally equivalent in the relevant context and yields predictable results. Holsworth expressly relies on a non-ionic hydrophilic PEG to enhance mixability/solubility in the GO-HA aqueous suspension (Holsworth [0029]); the OA does not make findings that polysorbate 20 performs the same role equivalently within a GO-HA/liposome system, and it draws polysorbate 20 from Boasberg, whose surfactant context (a collagen-binding targeting composition) differs. This is a fully-grounded challenge to the articulated reasoning, not a concession that surfactants are interchangeable generally.

• —Holsworth [0029]: surfactant is 'a non-ionic hydrophilic material such as polyethylene glycol (PEG)' that 'enhances mixability or solubility of hydrophobic substances in water'
• —OA §103: 'replace polysorbate 20 for PEG as surfactant because this is simple substitution of one known surfactant for another to obtain predictable results. MPEP 2143'

Risk PEG and polysorbate 20 are both common nonionic-type surfactants, so the examiner may readily supply an equivalence finding; this is a weaker, dependent-claim point best used to narrow the rejection rather than defeat it.

'The method of claim 61 or claim 62' where claims 61 and 62 are composition claims

For counsel to weigh: the examiner found claims 76-79 indefinite because they recite 'the method of claims 61 or claim 62' while 61/62 are composition claims. The examination-stage standard is BRI plus the § 2173.02 prongs (In re Packard / Ex parte Miyazaki), and the examiner already applied a reasonable construction — examining 76-79 as composition claims under compact prosecution — indicating the intended scope is reasonably ascertainable as a scrivener's 'method'/'composition' mismatch. The clean lever is a straightforward amendment conforming the dependency language to the composition claims; alternatively counsel may argue on the record that, under BRI, a PHOSITA would read 76-79 as composition claims with reasonably certain scope. Counsel should not argue that the §112(b) finding is improper merely because §103 was also applied — compact prosecution (MPEP § 2173.06(II)) permits the pairing.

• —OA §112(b): 'Claims 76-79 recite the method of claims 61 or claim 62, which however is a composition claim. Thus, the scope and boundary of claims 76-79 are unclear'
• —OA §112(b): 'For compact prosecution purpose, claims 76-79 are examined as composition claim.'

Risk The dependency mismatch is a genuine defect; the most efficient resolution is amendment, and arguing the claims are already definite risks leaving an easily-fixed formal issue unresolved. Do not cite Nautilus 'reasonable certainty' as the governing standard — cite the § 2173.02 examination standard.

the liposome/phosphatidylcholine/polysorbate 20/butylene glycol/ethanol features added to the '469 GO-HA/XAV939/HPC composition

For counsel to weigh: the double-patenting rejection over claims 1-12 of U.S. Patent No. 12,059,469 relies on the same Boasberg teachings — liposome, phosphatidylcholine, butylene glycol, polysorbate 20, ethanol — to bridge from the '469 claims (GO-HA + XAV939 + HPC, per the retrieved '469 claim text) to the present claims. To the extent the DP rejection depends on Boasberg supplying those features, it carries the same infirmity identified at rank 1 (those items sit in Boasberg's disparaged background). The '469 patent is fully grounded and its claims do not recite liposome, phosphatidylcholine, butylene glycol, polysorbate 20, or ethanol. As a practical matter this nonstatutory DP rejection can typically be obviated by a terminal disclaimer, a business decision for counsel; the substantive Boasberg point is preserved for the §103 rejection regardless.

• —'469 claim 1: 'a matrix component comprising a graphene oxide (GO) and hyaluronic acid (HA) conjugate (GO-HA)... XAV939... and water; where XAV939 constitutes from about 0.001 wt % to about 5 wt %'; claim 6 adds HPC thickener — no liposome/phospholipid recited
• —OA DP rationale: '...in view of Boasberg et al. teaching liposome formulation, phosphatidylcholine, butylene glycol, polysorbate 20 and ethanol...'

Risk A terminal disclaimer resolves nonstatutory DP without conceding the merits, but a TD has patent-term and common-ownership consequences counsel must weigh; arguing the Boasberg bridge fails does not avoid the DP if the examiner finds any independent basis for the added features.

the claimed composition as compared to claims 1-13, 15-17, 29-32 of copending Application No. 18/776,025

For counsel to weigh: the provisional nonstatutory double patenting rejection cites copending Application No. 18/776,025, whose text was not retrieved and did not resolve to a document on this record. Because the reference is unverifiable, its content must be taken as the examiner characterized it, and no missing-element or mischaracterization conclusion can be supported against it here. Counsel should obtain the actual claims of 18/776,025 to confirm what they recite before deciding whether to traverse or to file a terminal disclaimer; because the rejection is provisional, its ultimate disposition also depends on the prosecution of the copending application. This item is ranked last precisely because it turns on an unverifiable reference.

• —Reference grounding: 'Copending Application No. 18/776,025... UNVERIFIABLE — reference text was NOT retrieved... this number did not resolve to a document — verify it'
• —OA: 'This is a provisional nonstatutory double patenting rejection.'

Risk Do not treat any distinction from 18/776,025 as established — the claims were not seen. The examiner can maintain the provisional rejection until the copending claims are resolved; a terminal disclaimer or amendment in one application may be required.