DETAILED ACTION
Examiner acknowledges receipt of petition to revive and the reply filed 2/10/2026, in response to the non-final office action mailed 10/2/0224. A supplemental reply was filed 3/24/2026.
Examiner acknowledges receipt of the declaration filed 2/10/2026.
Claims 1-14 are pending. Claims 10 and 13 remain withdrawn from further prosecution for the reasons made of record.
Claims 1-9, 11, 12, and 14 are being examined on the merits in this office action.
In reply to this action, Applicant should amend the claims to indicate the correct status of claim 13; withdrawn.
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 .
Examiner Comment
A notice of abandonment for failure to reply to the office action mailed 10/21/2024, was mailed 5/15/2025. Applicant filed a petition to revive, reply to the outstanding action, and fees on 2/10/2026. The petition was granted 3/17/2026. See file wrapper.
Declaration under 37 CFR §1.132
The Declaration under 37 CFR 1.132 filed 2/10/2026 is insufficient to overcome the rejection of claims 1-9, 11, 12, and 14 based upon 35 USC 103 as set forth in the non-final office action mailed 10/21/2024. Please see the Response to Arguments section below the rejection.
Examiner expressly notes the information set forth in Exhibit B – p. 24 of the declaration is too pixelated and not legible:
PNG
media_image1.png
364
868
media_image1.png
Greyscale
Information Disclosure Statement- maintained
The IDS filed 12/24/2020 has been reviewed and considered. US Patent document 5 has been struck-through. The Patent No is incorrect. U.S. 1017556 issued in 1912 and relates to shoe making.
Response to Arguments
In the remarks filed 2/10/2026, applicant provides a patent number and states that Lin et al is not material to the patentability of the presently claimed leptin-drug conjugates and is submitted solely to correct the record (reply filed 2/10/2026 at p. 58).
Examiner contacted Applicant on 3/19/2026 to inform Applicant that a supplemental amendment was needed for the claims relating to claim formatting. Examiner further stated that a supplemental IDS was required to present any new references. Applicant did not file a new IDS with the supplemental response/amendment filed 3/24/2026.
A new IDS is required.
Nucleotide and/or Amino Acid Sequence Disclosures- withdrawn
The objection to the sequence disclosure is withdrawn in view of the amendment filed 2/10/2026.
Specification- withdrawn
The objection to the specification is withdrawn in view of the amendment filed 2/10/2026.
Drawings- withdrawn
The objection to the drawings is withdrawn in view of the amendment filed 2/10/2026.
Claim Objections- withdrawn
The objection of claims 1-4, 6-9, and 14 is withdrawn in view of the amendment filed 3/24/2026.
Claim Rejections - 35 USC § 112- withdrawn, in part
The rejection of dependent claims 2, 4, 8, and 9 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in part, in view of the amendment filed 3/24/2026.
Response to Arguments
Applicant's arguments filed 2/10/2026 and amendment filed 3/24/2026 with respect to the above objections and rejections have been fully considered and are persuasive. Therefore, the objections and rejections have been withdrawn.
Applicant's arguments filed 2/10/2026 and amendment filed 3/24/2026 have been fully considered but they are not persuasive with respect to the maintained objections.
Upon further consideration, a new ground(s) of objection is made in view of the amendment filed 3/24/2026.
An action on the merits is set forth herein.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
New Objections
Claim Objections- New objection
Claims 1, 4 and 6-9 are objected to because of the following informalities:
Claim 1 should be amended to recite “or” at lines 5-6: “4, or 5”.
Claim 4 should be amended to move the period at p. 13, line 3 up one line to line 2. The period should be recited after the last recited compound, not a separate line by itself.
Claim 6 should be amended to recite “wherein X3 is a therapeutic compound not recite the term “agent”.
Claim 7 should be amended to recite: “wherein X3 is selected”. The amendment filed 3/24/2026 eliminated a space between “X3” and “is”.
Claim 8 should be amended to include “and” between the last compounds. As presently written end of claim 8 recites “,.”. The comma at page 20, l. 5 should be deleted. The period at p. 20, l. 6 should be moved up one line to the end of line 5. The period should not be a line by itself.
Claim 9 should be amended to move the period at p. 41, line 5 up one line to line 4. The period should be recited after the last recited compound, not a separate line by itself.
Appropriate correction is required.
Maintained Rejections
Claim Rejections - 35 USC § 112- maintained
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-9, 11, 12, and 14 remain/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. This rejection is maintained from the office action mailed 10/21/2024, but has been amended to reflect claims filed 3/24/2026.
The metes and bounds of claim 1 and dependent claims 2-9, 11, 12, and 14 are deemed to be indefinite.
MPEP 2173.05(h) states: A Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members. Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196. If a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group "comprising" or "consisting essentially of" the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim.
In claim 1, the definitions of variables m and n are open groups of alternatives because there is no “or” between the last and second to last option. Dependent claims 2-9, 11, 12, and 14 fail to remedy this issue and are likewise rejected.
Claim 6 recites the limitation "the agent". There is insufficient antecedent basis for this limitation in the claim. Claim 6 depends from claim 1. Claim 1 recites “therapeutic compound”. Claim 1 does not recite the term “agent”.
To overcome this rejection, claim 6 should be amended to recite “wherein X3 is a therapeutic compound
Response to Arguments
Applicant did not set forth arguments relating to this rejection. However, the claims were amended in the reply filed 3/24/2026.
Regarding claim 1, the amendment filed 3/24/2026 did not address this part of the rejection.
Regarding claim 6, Applicant amended the claim to recite “the agent”. The rejection is maintained because crux of lack antecedent basis is not recitation of terms “the” or “an”, but recitation of the term “agent”. Independent claim 1 recites the term “therapeutic compound”. Claim 1 never recites the term “agent”. To overcome the rejection: Applicant should amend claim 6 to delete “agent” and insert therefore “therapeutic compound”.
The rejections are maintained for the reasons set forth herein.
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.
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 1-9, 11, 12, and 14 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Kraynov et al. (U.S. 20120149636- previously cited), in view of Park et al (Cell Death and Differentiation 23: 1296–1311 (2016) - previously cited), as evidenced by Tong et al (Nature 7: 5599 (2017) - previously cited), He et al. (Molecules 24:1855 (2019) - previously cited), and Jeffery (U.S. Patent No. 8,568,728- previously cited). This rejection is maintained from the office action mailed 10/21/2024, but has been amended to reflect claims filed 3/24/2026.
Kraynov et al teach modified human leptin polypeptides which can be conjugated via a linker to a biologically active molecule (abstract, paras. [0136]-[0138], [0557]-[0558]). Biologically active molecules include, but are not limited to, peptides, proteins, enzymes, small molecule drugs, dyes, lipids, nucleosides, oligonucleotides, cells, viruses, liposomes, microparticles and micelles. Classes of biologically active agents that are suitable for use with the invention include, but are not limited to, antibiotics, fungicides, anti-viral agents, anti-inflammatory agents, anti-tumor agents, cardiovascular agents, anti-anxiety agents, hormones, growth factors, steroidal agents, and the like (para. [0137]). Linkers can be bifunctional, allowing for attachment of different molecules at each terminus (paras [0021]-[0022], [0138], [0427], [0455]-[0460]). Kraynov et al teach inclusion of a second component, e.g., anti-obesity agents or diabetic agent (paras. [0422]-[0424]). The leptin protein can be modified for linker attachment at functional groups, e.g., the epsilon —NH2 of lysine, the sulfhydryl —SH of cysteine, the imino group of histidine (e.g., paras. [0124]-[0125]).
Although Kraynov et al teach that leptin can be conjugated to a biologically active agent, e.g., an anti-diabetic or anti-obesity agent, the reference does not teach that the teach that the agent is MLN4924/ pevonedistat.
Park et al teach that preadipocyte-to-adipocyte differentiation (adipogenesis) is a key process in fat mass increase and thus it is regarded as a compelling target for preventing or treating obesity. Of adipogenic hormone receptors, peroxisome proliferator-activated receptor gamma (PPARγ) has crucial roles in adipogenesis and lipid accumulation within adipocytes. Here we demonstrate that the NEDD8 (neuronal precursor cell expressed, developmentally downregulated 8)-based post-translation modification (neddylation) of PPARγ is essential for adipogenesis. During adipogenesis, NEDD8 is robustly induced in preadipocytes and conjugates with PPARγ, leading to PPARγ stabilization. When the neddylation process was blocked by NEDD8 inhibitor MLN4924, adipocyte differentiation and fat tissue development were substantially impaired (abstract). Park et al teach that MLN4924/ pevonedistat is an antidiabetic and can be used to treat obesity (abstract, pp. 1296, 1302-303). As evidenced by Tong et al., MLN4924 is a small molecule inhibitor of NAE and is also known in the art as pevonedistat (abstract, p. 2, 5).
Kraynov et al. does not teach that the linker corresponding to X2 is a glucuronide or dipeptide cleavable linker. However, this difference is obvious according to the rationale in MPEP § 2143.01(E): "Obvious To Try" – Choosing From a Finite Number of Identified, Predictable Solutions, With a Reasonable Expectation of Success.
First, at the time of the invention, there was a recognized problem or need in the art. Specifically, Kraynov et al. teach that the use of PEG derivatives of proteins can problematic in their synthesis and use. Some form unstable linkages with the protein that are subject to hydrolysis and therefore decompose, degrade, or are otherwise unstable in aqueous environments, such as in the bloodstream. To overcome this problem, Kraynov et al. use leptin modifications and linkers. However, Kraynov et al. did not explore or optimize the linker/polymer.
Second, at the time of the invention, there had been a finite number of identified, predictable potential solutions to the design of the linker between a drug and its targeting peptide. Specifically, He et al. review the field of peptide-drug conjugates which have the potential to enhance and broaden pharmacology while minimizing dose-dependent toxicology (abstract). He et al. teach that the linker is a critical part of a peptide-drug conjugate that integrates the peptide and small molecule medicinal agents. The linker maintains structural integrity of the conjugate during plasma circulation, preventing premature release of the drug that might result in adverse effects. The linker efficiently and specifically releases the drug at the site of the targeted tissue, enabling a tissue-targeted pharmacological effect (p. 14). He et al. teach hydrazone, ester, amide, disulfide, dipeptide, tripeptide, and glucuronide-based linkers provide a diverse set of linkers that can meet most needs in the assembly of peptide-drug conjugates for targeted delivery (Figure 8):
PNG
media_image2.png
620
389
media_image2.png
Greyscale
Third, one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success. Kraynov teaches that linkers included enzymatically unstable or degradable linkages that can be degraded by one or more enzymes (para [0136]). He et al. teach that it is relatively straightforward to make peptide-drug conjugates, given the established synthetic conjugation strategies (p. 19). He et al. teach that the dipeptide linkers such as Val-Cit are cleaved by intracellular cathepsin B and other proteases (p. 14). He et al. teach that the glucuronide based linker has the benefits of high aqueous solubility, serum stability, and facile drug release. The cleavage is promoted by glucuronidase which is abundantly present in lysosomes and overexpressed in certain tumors (p. 14).
The preparation of drug-glucuronide linker-ligand conjugates is detailed in the Jeffery patent. This patent discloses conjugates comprising a ligand bound to drug via a cleavable linker comprising a stretcher, glucuronide and self-immolative spacer and methods for making the same (col 2, lns 52-68). Jeffery teaches that the ligand can be a broad range of biomolecules (col 23, ln 24-43). With respect to the linker, the stretcher unit comprises a functional group capable of bonding to the ligand and a functional group capable of bonding to the adjacent portion of the linker. It may also contain a (CH2CH2O)1-10 group (col 19, ln 58 - col 22, ln 20).
In view of these findings, it would have been obvious to substitute the dipeptide or glucuronide linkers taught by He et al. for the linker leptin conjugates taught by Kraynov et al. The resulting conjugate would satisfy all of the limitations of claim 1. The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103."KSR, 550 U.S. at 421, 82 USPQ2d at 1397.
It would have been obvious to include the pevonedistat taught by Park et al. as the biologically active molecule in the leptin conjugates taught by Kraynov et al. and using the glucuronide linkers taught by He et al. and US 8,568,728. Kraynov et al expressly taught inclusion of a biologically active agent, e.g., an anti-diabetic or anti-obesity agent. The skilled artisan would have known from Park et al that MLN4924/ pevonedistat was an antidiabetic and can be used to treat obesity. One of ordinary skill in the art would have been motivated to do so in order to apply the advantages of leptin-directed delivery to an additional obesity/diabetic treatment, pevonedistat. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
With respect to instant Formula (I) in claim 1, m is 1, n is 1, X1 is leptin, and X3 is a therapeutic compound MLN4924/pevonedistat. Accordingly, the limitations of claims 1, 3, and 14 are satisfied.
Regarding claim 2, SEQ ID NO:2 of Kraynov et al has 100% identity with instant SEQ ID NO:1.
Regarding claims 4 and 9, Jeffery teaches the stretcher unit comprises a functional group capable of bonding to the ligand and a functional group capable of bonding to the adjacent portion of the linker. It may also contain a (CH2CH2O)1-10 group (col 19, ln 58 - col 22, ln 20), rendering obvious the cleavable linkers
PNG
media_image3.png
145
359
media_image3.png
Greyscale
(cleavable linker K-10) and
PNG
media_image4.png
161
406
media_image4.png
Greyscale
(cleavable linker K-12), and
PNG
media_image5.png
175
367
media_image5.png
Greyscale
(compound of B-52). With respect to claim 5, He et al. teaches conjugation to a cysteine or lysine in the peptide drug. Kraynov et al teach the linker attachment site can be a cysteine or lysine residue of leptin. Regarding claim 6, Park et al teach that MLN4924/ pevonedistat is an antidiabetic and can be used to treat obesity (abstract, pp. 1296, 1302-303). Regarding claims 7, 8, and 14, Park et al teach that MLN4924/ pevonedistat is a NEDD8 inhibitor (pp. 1301-1305). The resulting conjugate would satisfy all of the requirements of the elected species and of claims 11 and 12.
Claims 1-9, 11, 12, and 14 are rendered obvious by the teachings of the cited references.
Response to Arguments
Applicant traversed the rejection at pp. 58-62 of the reply filed 2/10/2026. Applicant asserts that the pending claims are directed to a defined protein-drug conjugate (PDC) in which: (i) the targeting moiety is leptin (SEQ ID NO:1); (ii) the payload is the NEDD8- activating enzyme inhibitor (NAEi) MLN4924 (pevonedistat); and (iii) the payload is coupled to leptin through a cleavable linker at a defined conjugation site (K12), such that leptin retains receptor-binding/activation delivers the payload intracellularly via receptor-mediated uptake. Applicant asserts that the cited references do not teach or render obvious the claimed construct (reply filed 2/10/2026 at pp. 58-59).
Applicant asserts that Kraynov does not disclose using leptin as a targeting ligand to deliver a different small molecule payload intracellularly that the reference does not identify NAEi compounds as payloads (reply at p. 59). Applicant asserts that the cited references do not provide any motivation the skilled artisan to select leptin for this targeting/delivery role in combination with a NAEi payload. Id.
Applicant alleges that the cited art teaches away from the claimed payload selection and provides no reasonable expectation of success. Applicant asserts that the cited references Park and Tong discuss systemic administration of MLN4924 (pevonedistat) can you not suggest conjugating the compound to a cytokine hormone (e.g., leptin), do not address preservation of leptin receptor binding/activation after conjugation, or disclose controlled intracellular release from a defined cleavable linker installed at a defined conjugation site on leptin (reply at p. 59). Applicant asserts that the art reports dose limiting toxicity concerns for MLN4924 which discourages routine use as a systemic anti-obesity therapeutic and underscores the need for a targeted delivery strategy (reply at p. 60).
Applicant states: “Park reports efficacy at 30 mg/kg (approximately 1.69 µmol per 25g mouse dose) and reports toxicity at 400 µg (approximately 0.9 µmol). In contrast, applicant leptin- MLN4924 PDC achieves efficacy at 293 pmol and 879 pmol per dose-orders of magnitude more payload exposure than systemic MLN4924-and those doses are non-toxic.” Reply at p. 60. Applicant asserts “dramatic improvement in therapeutic index” is not suggested by the art and is inconsistent with the cited combination of references.
With regard to linker selection and site-specific conjugation, applicant asserts hindsight reconstruction on the part of the office. Applicant asserts that linker design is a critical determinant of plasma stability, targeting ligand’s activity, intracellular cleavage kinetics, and payload release at the intended subcellular location (reply at p. 60). Applicant asserts that the cited references He and Jeffrey do not teach that skilled artisan would select a glucuronide linker architecture for a leptin targeted PDC with an NAE payload, at a site-specific K12 as claimed.
Applicant asserts that the amended claims recite a specific, functionally integrated PDC that the art does not teach or render obvious (e.g., retaining receptor binding/activation, intracellular delivery, stable in circulation, claimed structure) (reply at p. 61).
Applicant asserts that exhibit C [identified as exhibit B in the declaration] demonstrates that the claimed leptin-MLN4924 protein drug conjugates (PDCs) deliver unexpected results that a skilled physician would not reasonably predicted from the cited references. Applicant asserts that the data reports meaningful metabolic efficacy in a DIO mouse model, body weight reduction, improved fasting blood glucose, reduced LDL, at payload molar modes of approximately 293 and 879 pmol/dose. Applicant asserts that the results are unexpected in view of the systemic MLN4924 efficacy at 30 mg/kg (approximately 1.69 µmol payload per ~25g mouse) and reports toxicity at 400 µg (approximately 0.9 µmol) (improved efficacy at lower payload exposure with the claimed leptin-MLN4924 PDCs (reply at p. 61). Applicant alleges that the data rebuts the office actions premise that the claimed constructs would yield expected, predictable results (p. 62).
Applicant asserts the combined references do not provide a prima facie case of obviousness, and asserts teaching away in the art and unexpected results.. Id.
Declaration
The declaration asserts hindsight analysis, and that Kraynov’s primary focus is on leptin itself as the therapeutic agent, and not using leptin is a targeting ligand to mediate intracellular delivery of a payload (p. 3). Applicant asserts that Kraynov does not teach or suggest combining leptin with an NEDD8 inhibitor payload. Id. Applicant asserts cited references Park and Tong do not teach conjugating MLN4924 to leptin, address preservation of leptin receptor binding/activation, or suggest leptin receptor-mediated endocytosis for intracellular payload delivery (pp. 3-4).
Applicant asserts that linker selection and conjugation site selection are not routine substitutions. Applicant asserts the linker have functional properties: e.g., stable in circulation, preserve binding/activation to the target protein, enable efficient intracellular cleavage, avoid aggregation (p. 4). Applicant asserts that the cited reference He is a review listing diverse linker classes and that the “existence of multiple linker classes and trade-offs underscores that linker choice is context-dependent optimization”. Applicant asserts that “Jeffrey’s glucuronide linkers are taught largely in a different context” and do not provide guidance for the claimed leptin-targeted PDC and intracellular release of MLN4924 (p. 4).
Applicant asserts that there would not have been a reasonable expectation of success in conjugating MLN4924 to leptin through cleavable linker at defined sites would yield a safe and effective agent for chronic metabolic indications (p. 5). Applicant asserts MLN4924 and study primarily as mycology agent and systemic exposure was associated with dose limiting toxicity. Id. Applicant alleges that this creates a disincentive to employ MLN4924 4 disease treatment in that the claimed compounds would not have been predictable from the cited art. Id.
Applicant asserts unexpected results at pp. 5-6. Applicant states: Park reports systemic MLN4924 efficacy that 30 mg/kg (approximately 1.69 µmol per ~ 25g mouse) and reports toxicity at 400 µg (approximately 0.9 µmol). By contrast, the leptin- MLN4924 PDC demonstrates efficacy at approximately 293 pmol and 879 pmol per dose, and those PDC doses were non-toxic”. Applicant asserts the findings were unexpected and not suggested by the cited reference combination. Declaration at p. 5. Applicant asserts the unexpected results are commensurate with the scope of the amended claims i) leptin as X1, ii) cleavable glucuronide or dipeptide linker as X2, and iii) therapeutic payload X3 as MLN4924/pevonedistat (p. 6).
The declaration concludes that the references alone or in combination to not render the amended claims obvious, further referring to requirements of leptin receptor functional preservation, intracellular release of payload, and experimental evidence of “unexpected results”.
Examiner Rebuttal
Examiner has reviewed and considered applicants arguments and the declaration, but is not persuaded.
Examiner first notes that the instant claim scope is much broader than what is stated by applicant at page 58. The instant claim scope encompasses a genus of leptin polypeptide homologs, glucuronide or dipeptide cleavable linkers [variable chemical structures], and a therapeutic compound [undefined chemical composition]. The attachment sites between the leptin homolog, linker and therapeutic compound are undefined.
In response to applicant's argument related to leptin targeting and intracellular delivery via the leptin receptor, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., leptin receptor mediated targeting/delivery, maintain receptor binding/functionality, intracellular payload release) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). This further applies to reply at p. 60, section 4.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Kraynov et al teach modified human leptin polypeptides [reads on leptin homologs] which can be conjugated via a linker to a biologically active molecule (abstract, paras. [0136]-[0138], [0557]-[0558]). Biologically active molecules include small molecule drugs. Classes of biologically active agents that are suitable for use with the invention include, but are not limited to, antibiotics, fungicides, anti-viral agents, anti-inflammatory agents, anti-tumor agents, cardiovascular agents, anti-anxiety agents, hormones, growth factors, steroidal agents, and the like (para. [0137]). Linkers can be bifunctional, allowing for attachment of different molecules at each terminus (paras [0021]-[0022], [0138], [0427], [0455]-[0460]). Kraynov et al teach inclusion of a second component, e.g., anti-obesity agents or diabetic agent (paras. [0422]-[0424]). The leptin protein can be modified for linker attachment at functional groups, e.g., the epsilon —NH2 of lysine, the sulfhydryl —SH of cysteine, the imino group of histidine (e.g., paras. [0124]-[0125]). SEQ ID NO:2 of Kraynov et al has 100% identity with instant SEQ ID NO:1. Thus, Kraynov discloses leptin homolog conjugates, bi-functional enzymatically cleavable linkers, the sequence of instant SEQ ID NO:1, and linker attachment sites, e.g. leptin lysine and cysteine residues.
Park expressly teaches that MLN4924/ pevonedistat is an antidiabetic and can be used to treat obesity (abstract, pp. 1296, 1302-303).
He et al discloses glucuronide and dipeptide cleavable linkers. The reference provides further guidance and considerations for linkers relating to e.g., plasma stability, intracellular targeting and cleavage, potency requirements and maintaining functional target receptor interactions (e.g., pp. 14-17 and 19-21).
Jeffries provides detailed preparation of drug-glucuronide linker-ligand conjugates. This patent discloses conjugates comprising a ligand bound to drug via a cleavable linker comprising a stretcher, glucuronide and self-immolative spacer and methods for making the same (col 2, lns 52-68). Jeffery teaches that the ligand can be a broad range of biomolecules (col 23, ln 24-43). With respect to the linker, the stretcher unit comprises a functional group capable of bonding to the ligand and a functional group capable of bonding to the adjacent portion of the linker. It may also contain a (CH2CH2O)1-10 group (col 19, ln 58 - col 22, ln 20).
Thus, the cited references disclose each of the recited claim elements, as well as the positional/structural arrangements of the claimed leptin homolog, glucuronide cleavable linker, and therapeutic compound (pevonedistat) as set forth in claimed formula I. Please refer to the above 103 rejection for specific analysis.
With respect to the functional properties applicant discloses, e.g., retention of receptor binding/activation of conjugation, intracellular delivery and release, linker stability and circulation, structural design of the leptin PDC, the examiner finds no evidence from the prior art that suggests the combination of leptin [interact/bind to the leptin receptor], glucuronide cleavable linker [cleaved by glucuronidase which is abundantly present in lysosomes, as taught by He], and pevonedistat [antidiabetic/utility in obesity treatment] would be expected to interfere with each other during preparation, or use of the claimed PDC.
Contrary to applicant’s assertions, Park does not “teach away” from incorporating pevonedistat into the leptin conjugates of Kraynov. It is further noted that just because something “may occur” [potential toxicity] cannot be conflated with something that will, in fact, occur, much less be a basis to stagnate progression of science of peptide/protein therapeutics.
Furthermore, MPEP guidelines require a “reasonable” expectation of success, there is no requirement of a guarantee of success. Conclusive proof of efficacy is not required to show a reasonable expectation of success. Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). See MPEP § 2143.02.
Contrary to applicant’s assertions, Park et al do not disclose “toxicity at 400 µg (approximately 0.9 µmol)” - as indicated by applicant at pp 60 and 61.
Instead, Park discloses the following:
Obesity is developed through two different programs: adipocyte hyperplasia due to increased adipogenesis and adipocyte hypertrophy due to lipid accumulation.3 In childhood obesity, adipocyte hyperplasia largely contributes to the increase of fat volume. As the early stage of adipogenesis is blocked by the inhibition of neddylation, MLN4924 was expected to prevent childhood obesity rather than adult obesity. For this reason, we induced obesity in young mice. C57BL/6 male mice were fed with either normal control diet (NCD) or high-fat diet (HFD) for 12 weeks and were also injected intraperitoneally with vehicle or MLN4924 (30 mg/kg) twice a week. Amazingly, MLN4924 prevented HFD-induced overweight (Figure 7a). Moreover, MLN4924 did not reduce body weight in the NCD [normal control diet] group, indicating that the dose used is not toxic.
In the present study, MLN4924 is introduced as a PPARγ inhibitor that prevents obesity and glucose intolerance in young mice. However, since numerous anti-obesity drugs have been withdrawn from the market due to their adverse effects, the toxicity of MLN4924 should be carefully checked the preclinical stage during the drug development. MLN4924 makes a MLN4924-NEDD8 adduct by covalently binding to NEDD8, and the adduct inhibits the enzymatic action of NAE. Indeed, MLN4924 has successfully passed through preclinical tests and is under evaluation for clinical stages. A phase 1 study has been done on patients with acute myeloid leukemia and myelodysplastic syndromes. The patients were treated with a 60-min intravenous infusion of MLN4924 according to two different administration schedules, which were repeated every 21 days. Consequently, the majority of adverse effects were mild or moderate symptoms, such as pyrexia, chill, diarrhea, fatigue, and others. However, some dose-limiting toxicities, including neutropenia, thrombocytopenia and elevated aspartate transaminase, were also observed in both cohorts. Based on the patients' responses, the maximum tolerated dose (MTD) of MLN4924 was finally determined as either 59 or 83 mg/m2 in two cohorts. However, as MLN4924 has been tested as an anticancer drug, the tolerable upper limit of toxicity may be higher than that of developing anti-obesity drugs. This is why we treated mice with MLN4924 at a lower dose. Previously, MLN4924 was injected either daily at doses of 30 and 60 mg/kg or twice a week at a dose of 60 mg/kg in preclinical studies evaluating its anticancer effect. In this study, we reduced the dose of MLN4924 approximately by half because the drug was administered twice a week at a dose of 30 mg/kg. Even after being injected with MLN4924 for 12 weeks, all mice appeared healthy and active without weight loss in the NCD group. Also, there were no pathologic findings in the abdominal viscera (data not shown). Practically, we cannot simply compare the toxic doses of drugs between humans and mice because generally mice have much higher xenobiotic rates than humans.
Park at pp. 1302 and 1305-1306. Emphasis added. Park et al reports
cancer treatments administer higher MLN4924 doses than MLN4924 doses used in obesity treatment. Additionally, the “toxic” doses of MLN4924 in mice cannot necessarily be extrapolated to that of humans due to differences in species metabolism. Accordingly, applicant’s arguments relating to systemic MLN4924 and purported toxicity are unfounded.
Examiner notes the data presented is Exhibit B is too pixelated and difficult to decipher. The evidence of unexpected results presented in the declaration is only commensurate with the elected species wherein X1 is wild type human leptin (SEQ ID NO:1), and X3 is pevonedistat. The identity of the linker used in the leptin PDCs is unclear. The instant claim scope encompasses a genus of leptin homologs, glucuronide or dipeptide cleavable linkers [variable chemical structures], and a therapeutic compound [undefined chemical composition]. The attachment sites between the leptin homolog, linker and therapeutic compound are undefined.
Given the diversity in protein sequences permitted by the claimed genus of leptin homologs and the diversity in structure and function permitted by the claimed genus of therapeutic compounds, 1 of ordinary skill the art would not be able to predict whether such results asserted by applicant can be achieved with other species of X1, X2, and X3.
In submitting evidence asserted to establish unobvious results, the evidence relied upon should also be reasonably commensurate in scope with the subject matter claimed and illustrate the claimed subject matter “as a class” relative to the prior art subject matter “as a class.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971); In re Hostettler, 429 F.2d 464, 166 USPQ 558 (CCPA 1970). See, also, In re Lindner, 457 F.2d 506, 173 USPQ 356 (CCPA 1972).
It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D’Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992).
The weight attached to evidence of secondary considerations by the examiner will depend upon its relevance to the issue of obviousness and the amount and nature of the evidence. Note the great reliance apparently placed on this type of evidence by the Supreme Court in upholding the patent in United States v. Adams, 383 U.S. 39,148 USPQ 479 (1966). To be given substantial weight in the determination of obviousness or nonobviousness, evidence of secondary considerations must be relevant to the subject matter as claimed, and therefore the examiner must determine whether there is a nexus between the merits of the claimed invention and the evidence of secondary considerations. Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 305 n.42, 227 USPQ 657, 673-674 n. 42 (Fed. Cir. 1985), cert. denied, 475 U.S. 1017 (1986). The term “nexus” designates a factually and legally sufficient connection between the objective evidence of nonobviousness and the claimed invention so that the evidence is of probative value in the determination of nonobviousness. Demaco Corp. v. F. Von Langsdorff Licensing Ltd., 851 F.2d 1387, 7 USPQ2d 1222 (Fed. Cir.), cert. denied, 488 U.S. 956 (1988). See M.P.E.P. § 716.01(b).
The rejection is maintained for at least these reasons and those previously of record.
Relevant Art Not Relied Upon
Gao et al (Scientific Reports 7:41795, pp 1-152 (2017)) teach that c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family, has emerged as a promising target of drug design for treating obesity (pp. 1-2). Gao et al teach that administration of SR-3306, a brain-penetrant and selective pan-JNK (JNK1/2/3) inhibitor, reduced food intake and body weight (abstract, pp. 2-8).
Conclusion
No claims are allowed. Claims 1-14 are pending. Claims 10 and 13 are withdrawn.
Claims 1-9, 11, 12, and 14 are rejected.
Applicant's amendment necessitated the new ground(s) of objection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, LIANKO GARYU can be reached at 571-270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KRISTINA M HELLMAN/Examiner, Art Unit 1654
/JULIE HA/Primary Examiner, Art Unit 1654
Prosecution Insights