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 .
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.
Claim Status
Applicant’s amendment of 08/06/2026 is acknowledged. Claims 1, 2, 4, 7, 9, 11-12, 14, and 16-17 are amended, and claims 3 and 10 are cancelled. Claims 1-2, 4-9, and 11-20 are currently pending and are examined on the merits herein.
Priority
The instant application is a CON of U.S. Application No. 17/271,422 filed on
02/25/2021, which is a 371 of PCT/EP2019/072723 filed on 08/26/2019, and claims
foreign priority to EP18191027.4 filed on 08/27/2018 as reflected in the filing receipt
dated on 05/21/2025.
Information Disclosure Statement
Applicant’s Remarks dated 08/06/2026 are acknowledged. Applicant clarifies that the two NPL documents (50 pg. each) referenced by the Examiner on pg. 3 of the Office action dated 05/12/2026 relate to the same NPL reference (1) of the IDS submitted on 07/15/2025, noting that the reference was divided into three documents due to size. Because, as previously noted, Applicant has not provided an English translation of the documents and/or provided an explanation of the relevance of the documents as required under 37 CFR 1.98, the reference has only been considered to the extent of what was discernable in English (e.g., compound names, compound structures, portions of figures, etc.).
Previous Rejections/Objections
Applicant’s arguments filed 08/06/2026 have been fully considered. Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied as necessitated by Applicant’s amendment to the claims. They constitute the complete set of rejections and/or objections presently being applied to the instant application. Applicant’s arguments insofar as they pertain to the present grounds of rejections and/or objections are addressed herein.
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 4-9 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.
Claims 4-9 directly or indirectly depend from claim 3, which has been cancelled by Applicant. The claims are rejected as being indefinite because they are now incomplete. For examination purposes, the Examiner is interpreting claims 4 and 7, from which claims 5-6 and 8-9 respectively depend, as directly depending from claim 1, which now encompasses the features of cancelled claim 3.
Claim Rejections - 35 USC § 112(a)
Written Description Rejection
Claims 1-2, 4-9, and 11-20 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification discloses chemicals, such as specific PKC inhibitors (e.g., bisindolylmaleimide, staurosporine, etc.), specific PI3 kinase inhibitors (e.g., copanlisib, idelalisib, etc.), specific carbohydrates (e.g., N-acetyl-galactosamine, galactose, etc.), which meet the written description and enablement provisions of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. However, claims 1-2, 4-9, and 11-20 are directed to encompass PKC signaling pathway inhibitors and/or carbohydrate derivatives which only correspond in some undefined way to specifically instantly disclosed chemicals. None of these broader classes of PKC signaling pathway inhibitors or carbohydrate derivatives meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, due to lacking chemical structural information for what they are and chemical structures are highly variant and encompass a myriad of possibilities. The specification provides insufficient written description to support the genus encompassed by the claim. Note: MPEP 2163.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Univ. of Rochester v. G.D. Searle, 69 USPQ2d 1886, 1892 (CAFC 2004), further supports this by stating that:
The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. A description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) described even in terms of its functioning of lessening inflammation of tissues fails to distinguish any steroid from others having the same activity or function. A description of what a material does, rather than of what it is, usually does not suffice…. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. (Emphasis added).
With the exception of the above specifically disclosed chemical structures, the skilled artisan cannot envision the detailed chemical structure of the encompassed PKC signaling pathway inhibitors and carbohydrate derivatives regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003).
Therefore, only the above chemically structurally defined chemicals, but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The species specifically disclosed are not representative of the claimed genera because the genera are highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115).
Response to Arguments
Applicant’s arguments submitted on 08/06/2026 with respect to rejections under 35 U.S.C. 112(a) have been fully considered.
Applicant argues that the amendment to independent claim 1 to include the features of claims 3 and 10 overcomes the rejection because the Office does not provide specific arguments why the examples listed in claim 3 and 10 would not comply with the written description requirement and claims 2-20 appear to be rejected only for the reason that base claim 1 is rejected.
The Examiner respectfully disagrees. In the rejection, the Examiner specifically points out that Applicant only has support for specifically disclosed chemicals, such as specific PKC inhibitors (e.g., bisindolyImaleimide, staurosporine, etc.), specific PI3 kinase inhibitors (e.g., copanlisib, idelalisib, etc.), specific carbohydrates (e.g., N-acetyl-galactosamine galactose, etc.) but not broader classes of PKC signaling pathway inhibitors or carbohydrate derivatives. However, Applicant’s amended claim 1 still recites broader classes of PKC signaling pathway inhibitors (e.g., a PKC inhibitor, a PI3 kinase inhibitor, a MAPK inhibitor, a PLC inhibitor, a DAG level reducing agent, a siRNA, a shRNA, a miRNA, a modified oligo analogue, an antisense construct, or a RNAse H) and includes the limitation “derivatives thereof” in listing otherwise sufficiently specific carbohydrate targeting moieties. Thus, the instant claims still fail to meet the written description requirement because the specification lacks chemical structural information for what exact structures are encompassed by the broad claim language. Accordingly, the 112(a) rejection of claims 1-2, 4-9, and 11-20 is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4-6, and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over Martinac et al. (IAI, vol. 45 (suppl. 1), S1-S66; published: 2017; IDS of 07/15/2025) in combination with Gupta et al. (Drug Devel. and Indus. Pharm., vol. 39, pg. 1866-1873; published: 03/08/2012; IDS of 07/15/2025) as evidenced by Mayati et al. (Int. J. of Mol. Sci., vol. 18, pg. 1-22; published: 04/04/2017; PTO-892) and Grewal et al. (Nat. Med., vol. 14, pg. 1-18; published: 04/13/2010; IDS of 07/15/2025).
Martinac discloses a method for treating septic cholestasis comprising the intraperitoneal injection of the pan-protein kinase C (PKC) inhibitor Gö6850 into animals induced with sepsis [pg. S6, sec. 024, para. 2-5]. Treatment of septic cholestasis with Gö6850 resolves excretory function and increases survival, thereby emphasizing the importance of protein kinases in the development of liver failure during infection [pg. S6, sec. 024, para. 1 and 5].
Gö6850 is also known as bisindolylmaleimide-I, as evidenced by Mayati [pg. 7, para. 1], and thus reads on the claimed inhibitor of a PKC signaling pathway, as evidenced by instant claim 6.
However, Martinac does not expressly teach that the inhibitor is a component of a nanostructured delivery system comprising at least one carbohydrate moiety.
Gupta teaches that site specific-ligands like galactose (Gal), which is actively taken up by asialoglycoprotein receptors (ASGPRs) exclusively present on hepatic cells, are routinely ligated to polymeric nanoparticulate carriers to enhance target specificity and performance [pg. 1866, right col.; pg. 1867, left col.]. Accordingly, Gupta discloses Gal-conjugated poly lactic co glycolic acid (PLGA) nanoparticles, which the reference teaches can be used suitably as vehicles for delivery of bioactives specifically to the hepatic tissues and may be exploited in the effective management of various liver disorders [abstract].
Regarding claim 1: It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to deliver the Gö6850 of Martinac using the Gal-PLGA nanoparticles of Gupta in order to ensure site-specific delivery of the bioactive to the liver and prevent off-target biodistribution, which is a reasonable risk given that Gö6850 is a pan-PKC inhibitor, i.e. targets multiple PKC isoforms and is not liver specific. Further, it would have been prima facie obvious to administer the resulting nanostructured delivery system to a patient diagnosed with septic cholestasis using the method of Martinac because the reference highlights the clinical relevance of Gö6850 in effectively treating animals, i.e. patients, having the condition. Applying a known technique to a known method ready for improvement to yield predictable results is recognized as a rationale supporting the conclusion of obviousness. See MPEP § 2143 and KSR International Co. V. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385, 1395-97 (2007).
Regarding the recitation “nanostructured delivery system is adapted for lowering or inhibiting PKC in liver cells”: Applicant’s instant disclosure provides no limiting structural definition of how a nanostructured delivery system can be “adapted for” the intended use. As such, the limitation is interpreted as a mechanistic outcome flowing naturally from administering the same nanostructured delivery system structure to a patient diagnosed with septic cholestasis. Because the prior art combination teaches the same patient being administered the same active agent by the same delivery system as claimed, the prior art method would necessarily lower or inhibit PKC in liver cells.
Regarding claim 2: It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer the nanostructured delivery system taught by the combined references by injecting it into a patient because Martinac teaches that this method is effective in delivering Gö6850 to treat septic cholestasis, and Gupta supports that Gal-PLGA nanoparticles may also be delivered by injection [pg. 1869, left col.].
Regarding claims 4-6: Gö6850, also known as bisindolylmaleimide I, reads on the claimed PKC inhibitor which directly inhibits the PKC pathway, as evidenced by the instant claims.
Regarding claims 13-17: PLGA, which is a polyester, reads on the claimed carrier, as evidenced by instant claims 16-17.
An ordinarily skilled artisan would reasonably expect success in combining the teachings of Martinac and Gupta to treat septic cholestasis because Gupta teaches that the galactose-conjugated PLGA nanocarrier is designed to target bioactives, i.e. any bioactives, to liver cells through recognition of Gal by liver-specific ASGPRs. ASGPRs are known to be expressed during sepsis, as evidenced by Grewal [pg. 4, para. 2-5]. Additionally, both references teach administration of bioactives to a patient via injection.
Claims 1-2, 4-9, and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over Martinac et al. (IAI, vol. 45 (suppl. 1), S1-S66; published: 2017; IDS of 07/15/2025) in combination with Gupta et al. (Drug Devel. and Indus. Pharm., vol. 39, pg. 1866-1873; published: 03/08/2012; IDS of 07/15/2025), as applied to claims 1-2, 4-6, and 13-17 above, and further in view of Recknagel (PLOS Med., vol. 9, pg. 1-17; published: 11/13/2012; IDS of 07/15/2025) and as evidenced Mayati et al. (Int. J. of Mol. Sci., vol. 18, pg. 1-22; published: 04/04/2017; PTO-892) and Grewal et al. (Nat. Med., vol. 14, pg. 1-18; published: 04/13/2010; IDS of 07/15/2025).
The combination of Martinac and Gupta as evidenced by Mayati and Grewal teaches the invention(s) of claims 1-2, 4-6, and 13-17 as discussed in detail above and further incorporated herein.
The prior art combination does not expressly teach that the inhibitor indirectly inhibits the PKC pathway as recited in claims 7-9.
Recknagel teaches that phosphatidylinositol-3-kinases (PI3Ks) are essential for regulation of hepatobiliary transport, and failure of this transport process underlies sepsis-associated cholestasis [pg 2., left col.]. Recknagel teaches that Mrp2 transporters, specifically, are critically involved in functional measures of cholestasis and their down-regulation is closely associated with prognosticated non-survivors [pg. 14, left col.]. Under septic-like inflammatory conditions, inhibition of PI3Kγ with wortmannin or AS605240 in hepatocytes significantly represses loss of membrane-bound Mrp2 [pg. 10, right col.]. The teachings of Recknagel expressly suggest that inhibition of PI3Kγ may, thus, alleviate sepsis-associated cholestasis [pg. 17, right col.].
Wortmannin and AS605240 each read on the claimed PI3 kinase inhibitor which indirectly inhibits the PKC pathway, as evidenced by the instant claims.
Regarding claims 7-9: It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the nanostructured delivery system in the method taught by the combination of Martinac and Gupta by further including a PI3K inhibitor, such as wortmannin or AS605240, to produce a composition for treating septic cholestasis. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Note: MPEP 2144.06.
Moreover, one of ordinary skill in the art would be motivated to combine PKC and PI3K inhibitors, which have two different mechanisms of action, to achieve a more comprehensive therapeutic effect than would be expected by targeting either kinase individually. An ordinarily skilled artisan would reasonably expect success because both PKC and PI3K are taught in the art as viable therapeutic targets for septic cholestasis.
The Examiner notes that the instant claim language “nanostructured delivery system comprises” recited in claim 1 allows for the inclusion of more than one PKC signaling pathway inhibitor.
Claims 1-2, 4-6, 11-18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Martinac et al. (IAI, vol. 45 (suppl. 1), S1-S66; published: 2017; IDS of 07/15/2025) in combination with Gupta et al. (Drug Devel. and Indus. Pharm., vol. 39, pg. 1866-1873; published: 03/08/2012; IDS of 07/15/2025), as applied to claims 1-2, 4-6, and 13-17 above, and further in view of D’Souza et al. (J. of Controlled Release, vol. 203, pg. 126-139; published: 02/18/2015; IDS of 07/15/2025) and as evidenced by Mayati et al. (Int. J. of Mol. Sci., vol. 18, pg. 1-22; published: 04/04/2017; PTO-892) and Grewal et al. (Nat. Med., vol. 14, pg. 1-18; published: 04/13/2010; IDS of 07/15/2025).
The combination of Martinac and Gupta as evidenced by Mayati and Grewal teaches the invention(s) of claims 1-2, 4-6, and 13-17 as discussed in detail above and further incorporated herein.
The prior art combination does not expressly teach that the carbohydrate targeting moiety is N-acetyl-galactosamine (GalNAc) or a multivalent or trivalent construct as recited in claims 11-12 and 18. Further, the prior art combination does not expressly teach wherein the inhibitor is covalently attached to the carbohydrate targeting moiety or polymer as recited in claim 20.
D’Souza, interested in (ASGPR)-mediated hepatocyte targeting, teaches that GalNAc ligand exhibits 10- to 50-fold higher affinity than Gal in inhibiting the binding of asialoorosomucoid (ASOR), which is an endogenous natural ASGPR ligand [abstract; pg. 128-129]. Further, the references teaches that trivalent and hexavalent GalNAc have exhibited high uptake efficiency, while increasing the number of GalNAc units above three provided only minor enhancement in overall affinity [pg. 129].
Regarding claims 11-12 and 18: It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the nanostructured delivery system in the method taught by the combination of Martinac and Gupta by substituting the Gal carbohydrate moiety with a trivalent GalNAc moiety taught by D’Souza. One of ordinary skill in the art would have been motivated to substitute with trivalent GalNAc in order to improve drug targeting by increasing the affinity of the nanostructured delivery system for ASGPRs. There is a reasonable expectation of success because D’Souza teaches that ligands comprising GalNAc show much higher affinity for ASGPRs than Gal-modified ligands, and trivalent GalNAc specifically exhibits high uptake efficiency.
Regarding claim 20: D’Souza further teaches a variety of drug-ligand conjugates suitable for targeting ASGPRs, including examples of small molecules conjugated to Gal-poly(lactic-co-glycolic acid) (PLGA) [pg. 131, table 2]. These covalent conjugates can easily pass through liver sinusoids to hepatocytes, thereby facilitating receptor-mediated endocytosis [pg. 131, table 2]. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the nanostructured delivery system in the method taught by the combination of Martinac and Gupta by covalently attaching Gö6850 to the galactose-conjugated PLGA, as taught by D’Souza. One of ordinary skill in the art would have been motivated to form a drug-ligand conjugate in order to enhance hepatocyte uptake of Gö6850 by ASGPRs. There is a reasonable expectation of success because D’Souza teaches a variety of ASGPR-targeted drug-ligand conjugates, including those bound to galactose-conjugated PLGA.
Claims 1-2, 4-6, and 11-20 are rejected under 35 U.S.C. 103 as being unpatentable over Martinac et al. (IAI, vol. 45 (suppl. 1), S1-S66; published: 2017; IDS of 07/15/2025) in combination with Gupta et al. (Drug Devel. and Indus. Pharm., vol. 39, pg. 1866-1873; published: 03/08/2012; IDS of 07/15/2025) and in view of D’Souza et al. (J. of Controlled Release, vol. 203, pg. 126-139; published: 02/18/2015; IDS of 07/15/2025), as applied to claims 1-2, 4-6, 11-18, and 20 above, and further in view of Mayati et al. (Int. J. of Mol. Sci., vol. 18, pg. 1-22; published: 04/04/2017; PTO-892) and as evidenced by Grewal et al. (Nat. Med., vol. 14, pg. 1-18; published: 04/13/2010; IDS of 07/15/2025).
The combination of Martinac, Gupta, and D’Souza as evidenced by Mayati and Grewal teaches the invention(s) of claims 1-2, 4-6, 11-18, and 20 as discussed in detail above and further incorporated herein.
The prior art combination does not expressly teach that the PKC inhibitor is midostaurin as recited in claim 19.
Mayati teaches that protein kinases C (PKCs) are implicated in the membrane insertion of bile acid transporters in the liver and, as such, targeting PKC-related signaling pathways using PKC activators or inhibitors is an attractive therapeutic approach for treating cholestasis [abstract; pg. 13, sec. 8]. Mayati acknowledges bisindolylmaleimide-I (i.e., Gö6850) as a known PKC inhibitor and further teaches midostaurin as an example of a new pan-PKC inhibitor [pg. 7, para. 1; pg. 12, table 4].
Regarding claim 19: It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the nanostructured delivery system in the method taught by the combination of Martinac, Gupta, and D’Souza by substituting Gö6850 with any known PKC inhibitor, such as midostaurin. It would have been obvious and there is a reasonable expectation of success because inhibition of PKC is well-recognized in the art as a clinically relevant approach for treating cholestasis, including septic cholestasis, and it is within the skillset of an ordinarily skilled artisan to test any known PKC inhibitor and determine its therapeutic efficacy. A person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Response to Arguments
Applicant’s arguments submitted on 08/06/2026 with respect to rejections under 35 U.S.C. 103 have been fully considered but were not found to be persuasive.
Applicant argues that because Martinac does not disclose or suggest selectively targeting the liver, it was not foreseeable that changing the systemic administration of the PKC inhibitor into a targeted delivery method would be effective for treating septic cholestasis. Applicant further argues that there is no teaching in Gupta that “any bioactive” may be delivery via this method into cells, asserting that Gupta only centers on acyclovir. These arguments were not found to be persuasive.
Septic cholestasis is a liver-specific disorder. Gö6850 is known to treat septic cholestasis but is a pan-PKC inhibitor, i.e., targets multiple PKC isoforms and is not liver specific. Gupta expressly teaches that Gal-PLGA nanoparticles “can be used suitably as vehicles for delivery of bioactives”—not just acyclovir—"specifically to hepatic tissues and thus may be exploited in the effective management of various liver disorders” [Gupta, abstract; previously cited]. Because Gupta’s delivery system has been shown to augment bioavailability, increase residence time, and enhance the delivery of a model bioactive [abstract; previously cited], an ordinarily skilled artisan would reasonably expect that it would be able to release a sufficient amount of another bioactive, such as the Gö6850 of Martinac, to treat the liver disorder septic cholestasis.
Applicant further argues that one of ordinary skill in the art would not have expected to achieve effective treatment of septic cholestasis via ASGPR targeting because sepsis conforms with the release of cytokines, as noted by Martinac, and cytokines reduce the expression and functioning of ASGPR, as evidenced by Treichel (IDS of 07/15/2025). Applicant further asserts that Grewal is not suitable evidence to assert that ASGPRs are expressed during septic cholestasis because the reference is directed to S. pneumoniae sepsis. These arguments were not found to be persuasive.
Applicant has provided no evidence that the cytokines evaluated in Treichel are the same as those released during septic cholestasis or that the concentrations of cytokines employed in Treichel are physiologically relevant in the context of septic cholestasis. Several parameters in Treichel appear to influence ASGPR expression and function, including duration of cytokine exposure and cytokine concentration, some of which actually increase ASGPR function [Treichel, Table 1, Fig. 1-4]. With the exception of an excessively high concentration (e.g., 103 U/ml) of IL-2 specifically, Treichel’s studies demonstrate that at least ~20% of ASGPR expression and/or function is maintained across all cytokine exposure conditions. Of particular note, cell surface ASGPR expression does not appear to be affected by increasing concentrations of cytokine over 24 hours [Fig. 8].
Based on these data, an ordinarily skilled artisan would reasonably expect that a nanodelivery system that targets ASGPR at the liver cell surface would indeed be able to bind the receptor and deliver a therapeutic. The Examiner also points out that Treichel is not drawn to septic cholestasis or even sepsis more generally. Using the same rationale with which Applicant used to purport that Grewal is not suitable evidence, the argument can be made that Treichel is not suitable evidence to support the conclusion that ASGPRs are not expressed during septic cholestasis. Grewal, on the other hand, supports that ASGPRs are known to be expressed in hepatocytes during sepsis in the liver. When all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Applicant further argues that claims 7-9, 11, 12, 18, and 19 are patentable for at least the same reasons as pointed out above regarding Martinac and Gupta. The Examiner respectfully disagrees for the same reasons discussed in detail above.
Applicant further argues that D’Souza is silent with regard to any drug delivery using CTM-targeting on ASGPR to treat septic liver cholestasis and asserts this is a further indication that one of ordinary skill in the art would not have been expected to achieve an effective treatment of septic cholestasis via ASGPR based targeting. This argument was not found to be persuasive.
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). In this case, D’Souza is drawn to the relevant topic of ASGPR-mediated hepatocyte targeting. The reference provides clear motivation to incorporate a trivalent GalNAc targeting moiety into the nanodelivery system taught by the combination of Martinac and Gupta because trivalent GalNAc has an increased affinity for ASGPRs and high uptake efficiency compared to the Gal moiety. Based on the combined prior art teachings, an ordinarily skilled artisan would reasonably expect that the resulting system would be capable of effectively delivering a PKC inhibitor, which is known to treat septic cholestasis, via ASGPR based targeting.
Applicant further argues that Mayati is drawn to cholestasis and cites paragraphs 0010-0016 of the instant specification to note it is warned in the literature not to submit immunosuppressants in the case of concurrent sepsis. The Examiner notes, however, that these paragraphs specifically warn against systemically administrating these inhibitors in the presence of an infection or inflammation of the patient [instant spec., pg. 5]. In the instant case, the prior art combination teaches a targeted delivery system, particularly to avoid the known risks associated with systemic administration of a pan-PKC inhibitor.
Because the prior art combination teaches administration of the same nanostructured delivery system comprising the same PKC inhibitor to the same patient population as instantly claimed, the Examiner maintains that a sufficiently strong prima facie case of obviousness exists. Therefore, the prior art rejections are maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-2, 4-9, and 11-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,472,259 B2 in view of D’Souza et al. (J. of Controlled Release, vol. 203, pg. 126-139; published: 02/18/2015; IDS of 07/15/2025) and Recknagel (PLOS Med., vol. 9, pg. 1-17; published: 11/13/2012; IDS of 07/15/2025).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of US ‘259 recite a method of treating septic cholestasis comprising administering a pharmaceutically effective amount of a nanostructured delivery system to a patient diagnosed with septic cholestasis [see copending claim 22]. The delivery system comprises an inhibitor of a protein kinase C (PKC) signaling pathway, at least one polymethine dye, and a carrier, and is adapted for treating septic cholestasis by lowering or inhibiting PKC in liver cells [see copending claims 1 and 22].
The claims of US ‘259 differ from the instant claims in that they do not recite the at least one carbohydrate targeting moiety recited in instant claims 1, 11-12, 18, and 20, the injecting step recited in instant claim 2, or the specific inhibitors recited in instant claims 7-9.
The teachings of D’Souza and Recknagel are as set forth above and further incorporated herein.
Regarding the carbohydrate targeting moiety recited in claims 1, 11-12, 18, and 20: It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the nanostructured delivery system in the method recited in US ‘259 claims by including the trivalent GalNAc moiety taught by D’Souza. One of ordinary skill in the art would have been motivated to incorporate the moiety in order to improve drug targeting by increasing the affinity of the nanostructured delivery system for ASGPRs, which are exclusively present on hepatocytes.
Regarding claim 2: It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention administer the nanostructured delivery system by injecting it into a patient because D’Souza teaches it is a routine delivery method for administering carbohydrate-modified polymers for targeting ASGPRs [pg. 130, Table 1].
Regarding claims 7-9: It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the nanostructured delivery system in the method taught by the combination of US ‘259 claims and D’Souza by further including a PI3K inhibitor, such as wortmannin or AS605240, to produce a composition for treating septic cholestasis. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Note: MPEP 2144.06.
Moreover, one of ordinary skill in the art would be motivated to combine the PKC and PI3K inhibitors, which have two different mechanisms of action, to achieve a more comprehensive therapeutic effect than would be expected by targeting either kinase individually. An ordinarily skilled artisan would reasonably expect success because both PKC and PI3K are taught in the art as viable therapeutic targets for septic cholestasis.
The Examiner notes that the instant claim language “nanostructured delivery system comprises” recited in claim 1 allows for the inclusion of more than one PKC signaling pathway inhibitor, as well as the polymethine dye recited in the claims of US ‘259.
There is a reasonable expectation of success because all techniques are known in the art to be useful for improving drug targeting to liver cells and/or to be viable therapeutic strategies for treating septic cholestasis.
Response to Arguments
The rejection on the grounds of non-statutory double patenting presented above are maintained since Applicant has not made any substantive arguments in the Remarks filed on 08/06/2026 traversing the rejection.
Conclusion
No claim is allowed.
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 SARAH CLINKSCALES WISTNER whose telephone number is (571)270-7715. The examiner can normally be reached Monday - Thursday 8:00 AM - 5:00 PM ET.
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/SARAH C WISTNER/Examiner, Art Unit 1616
/Mina Haghighatian/Primary Examiner, Art Unit 1616
