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 .
Priority
The application claims priority to provisional applications 63/090005, 63/158672, and 63/173130 filed on 09 October 2020, 09 March 2021, and 09 April 2021, respectively. The current application is a continuation of PCT/US2021/054234, filed on 08 October 2021. The effective filing date is 09 October 2020.
Information Disclosure Statement
The information disclosures (IDS) filed on 06 April 2023, 07 August 2024, and 16 March 2026
Status of Application, Amendments, and/or Claims
Claims 1-71 are the original claims filed on 06 April 2023. In the amendment of 31 August 2023, claims 5-12, 16, 18, 20-36, 38-43, 46, 48, 49, 52, 54-57, 59-61, and 65-69 were cancelled and claims 1-4, 13-15, 17, 19, 37, 44, 45, 47, 50, 51, 53, 58, 62-64, 70, and 71 were amended. An office action requiring the election of species was filed on 15 December 2025, and the applicant was required to elect species regarding the conjugated polymer and the form of cancer to be treated. In the communication 16 March 2026, the applicant elected regioisomeric structures XIIA and XIIIA for claim 19 and an immune-reactive solid tumor for claim 47, and subsequently selected colorectal cancer for claim 53. Upon further consideration, the election of species, as applied to claim 50, regarding the form of cancer to be treated has been withdrawn, and the affected claims has been rejoined. In this communication, claims 45, 63, and 64 were cancelled, claims 1-4, 13-15, 17, 19, 44, 47, 50, 51, 53, 58, 62, 70, and 71 were amended, and claims 72-77 were added. Claims 1-4, 13-15, 17, 19, 37,44, 47, 50, 51, 53, 58, 62, and 70-77 are pending and the subject of this office action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 47, 50, 51, and 53 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Following the communication, filed on 16 March 2026, the applicant has added new material, in the form of the phrase “immune-reactive” cancer. Neither the specification nor the claims (past or present) define what is meant by this term, and as such the scope of the related claims is indefinite. As interpreted by the examiner, for the purposes of identifying prior art, the phrase was taken at the broadest reasonable interpretation, cancer.
Since all claims, following claim 1, are dependent on claim 1, they are rejected, until claim 1 is amended or the subsequent claims are written to be independent of the rejected claim.
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.
Claims 1-4, 13-15, 17, 19, 37, 44, 47, 58, 62, and 70-77 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019028425 A1 (herein Ptacin) in view of Tang A, Harding F. (2019) The challenges and molecular approaches surrounding interleukin-2-based therapeutics in cancer. Cytokine X. 2018 Dec 10;1(1):100001 (herein Tang) and Stauber DJ, et al. (2006) Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2788-93 (herein Stauber), with Diab A, et al. (2020) Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). Cancer Discov. 2020 Aug;10(8):1158-1173 (herein Diab) and Ramil CP, Lin Q. (2013) Bioorthogonal chemistry: strategies and recent developments. Chem Commun (Camb). 2013 Dec 7;49(94):11007-22 (herein Ramil) providing additional evidentiary value.
In regard to claim 1, Ptacin teaches interleukin (e.g. IL-2) bioconjugates and their use in the treatment of one or more indications (Abstract). The IL-2 bioconjugates are taught to have one or more unnatural amino acid at a position that reduces receptor signaling potency to interleukin 2 receptor βγ (IL-2Rβγ), but retain significant activation of interleukin 2 receptor αβγ (IL-2Rαβγ) ([0005]). The unnatural amino acid(s), in certain embodiments, is/are taught to comprise a reactive group for chemistry used in site-selective biorthogonal reactions (i.e. copper-free alkyne-azole triazole-forming reactions) ([0077]). Embodiments, in which the conjugation reaction comprises a reaction between an azide and a strained alkyne, are taught ([0185]). It is also taught that the azide group may be contained on the unnatural amino acid and that the unnatural amino may be N6-azidoehthoxy-L-lysine (AzK) (relevant to instant claim 14) ([0005-0006] and claim 14), and that the strained alkyne may be a cycloalkyne ([0185]). The conjugating moiety is taught to contain a water-soluble polymer, which may comprise polyethylene glycol (PEG), and may be capped, as exemplified by mPEG ([0005], [0127], and claims 18 and 19). Several exemplary pegylated IL-2 compound are disclosed, comprising IL-2 conjugated to moieties comprising a water-soluble polymer with an approximate molecular weight of 30 kDa (relevant to instant claim 13) (Table 2, [0316]). The bioconjugates, disclosed in Ptacin, are suggested for use in the treatment autoimmune diseases or disorders, and as such comprise mutations aimed at increasing IL-2 affinity towards Treg cells, via increasing the affinity of the modified IL-2 towards IL-2Rαβγ ([0193-0200]).
Ptacin does not teach the use of IL-2 conjugates as method for treating immune-reactive cancer (e.g. colorectal cancer) and or stimulating CD8+ T cells and/or NK cells, without causing Grade 2 or higher vascular leak syndrome, comprising administering to a human subject about 8 μg/kg – 40 μg/kg, wherein the IL-2 conjugate comprises an IL-2 polypeptide comprising the amino acid sequence of SEQ ID NO:1, in which position P64 of the reference sequence is replaced by the structure of Formula (IA). Ptacin also does not teach an engineered form of IL-2 that has reduced affinity towards IL-2Rαβγ.
Tang et al provide a review of challenges associated with IL-2 therapy for various immune-reactive cancers and strategies to overcome these challenges (Abstract). One challenge, noted by the authors, is the extremely short serum half-life of IL-2 (in the order of minutes to hours), which creates the requirement for extremely rigorous dosing regimens (Section 2 paragraph 5). This short half-life is taught to result from rapid IL-2 clearance across the glomerular filtration barrier in the kidneys, owing to the high permeability of IL-2 to the barrier (due to its small size). Tang teaches that one strategy, that has been pursued to address this challenge, has been pegylation of recombinant IL-2 (Section 3.5).
Tang also teaches that IL-2 possesses an interesting duality in regard to immune function, as it is capable of acting as both an immune suppressor and an immune activator (Section 1 paragraph 5). Tang teaches that IL-2 mutants have been engineered to bias IL-2 binding towards specific IL-2R sub-units, resulting in either immune activation (via decreased IL-2Rαβγ affinity) or immune suppressor (via either increased IL-2Rαβγ affinity or decreased IL-2Rβγ affinity) (Section 3). It is taught that, by reducing IL-2 affinity towards IL-2Rαβγ, one is able to direct IL-2 binding towards Teff cells, such as CD8+ and NK cells (leading to increased Cd8+ T cell and NK cell expansion), while limiting interaction with immunosuppressive Treg cells (relevant to instant claims 58 and 74) (Section 3.1.1). This cell type-directed bias is taught to be the result of disruption in the IL-2 - IL-2Rα interface, and the authors highlight past strategies targeting residues at or near the IL-2 – IL-2Rα interface. Tang also notes that previous studies indicate that an additional effect of disrupting IL-2Rαβγ binding is a reduction in vascular leaking (relevant to instant claim 74) (Section 3.2).
Stauber relates to the analysis of a 3.0 Å crystal structure of the trimeric IL-2Rαβγ assembly in complex with IL-2 (Abstract). In this study, the various subunit interfaces are characterized (Results). Of particular relevance to the current application, is the analysis of the IL-2 – IL-2Rα interface (Results: Structure of IL-2Rα and Its Interface with IL-2). It is taught that IL-2Rα folds into two “sushi-like” domains, D1 and D2, that form five-stranded β-sheet sandwiches. D1 is shown to account for the majority of the total buried surface area between IL-2Rα and IL-2. The IL-2 – IL-2Rα interface comprises a polar periphery and a hydrophobic center, comprising IL-2Rα residues L2, M25, L42, and Y43, which pack with IL-2 residues F42, F44, Y45, P65 (equivalent to P64 in SEQ ID NO: 1 of the current application), and L72.
It would have been obvious to one skilled in the art, at the effective filing date, to combine the teachings of Ptacin (a method of bioconjugating IL-2 using Strain-Promoted Alkyne-Azide Cycloaddition (SPAAC) click chemistry), Stauber (identification of critical IL-2 – IL-2Rα interface residues), and Tang (strategy to bias IL-2 binding towards NK and CD8+ cells). Ptacin provides a strategy for site-specific bioconjugation of IL-2 through click chemistry, specifically SPAAC. This general strategy is widely used in the art, as evidenced by the 2022 Nobel Prize in Chemistry being awarded to Carolyn R. Bertozzi, Morten Meldal, and K. Barry Sharpless, for its development. Additionally, Formula IA, referenced in claim 1, is the product of two commonly used SPAAC reagents (Azk and DBCO). The use of AzK is taught by Ptacin (([0005-0006] and claim 14). The use of DBCO would have been obvious to one skilled in the art, based on Ptacin’s suggestion of a cycloalkyne in the SPAAC reaction ([0185]), because as taught by Ramil, DBCO (also known as DIBAC) possesses the fast kinetics of DIBO, a reagent taught by Ptacin ([0185]), while also possessing improved hydrophilicity (Page 4 paragraph 2). In regard to the structure of the linker, referenced as either Z or Y in claim 1, the disclosed structures would have been the result of reactions, aimed at producing a PEG reagent suitable for use in SPAAC (DBCO-mPEG), using widely available commercial products (e.g. DBCO-amine or DBCO-acid reacted with carboxylic-terminated PEG or amine-terminated PEG, respectively, with the appropriate activating agents, and illustrated below), that would have been obvious and routine to one skilled in the art, at the time of filing. This reagent would result in a q value of one in relation to instant claims 1, 14, 17, 19, and 37.
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Furthermore, the targeting of P64, in relation to SEQ ID NO:1 of the current application, would have been obvious to one skilled in the art based on the teachings of Stauber, in which five IL-2 residues that contribute to the hydrophobic center of the IL-2 – IL-2Rα interface (F42, F44, Y45, P65, and L72) are identified. It would have been reasonable to try substituting P65 (equivalent to P64 in SEQ ID NO:1 of the current application), one of only five possible options, with an unnatural amino acid, for the purpose of altering IL-2R sub-unit affinity. The prior art, namely Tang, teaches motivation for the IL-2 modifications claimed in the current application. By decreasing IL-2 affinity towards IL-2Rαβγ, which Stauber teaches would likely result from modifying position 64, and increasing the serum half-life of IL-2 by decreasing the permeability of the molecule across the glomerular filtration barrier, via conjugation with PEG polymers, one would address several known issues leading to toxicity of IL-2 therapy in immune-reactive cancers. When summarizing the teachings described above, one would arrive at a conjugation reaction, illustrated below, that results in a product encompassing the limitations referenced in instant claims 14, 17, and 19.
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In regard to dose range and administration schedule of the IL-2 bioconjugate, by increasing the serum half-life of the IL-2 therapeutic, one is able to relax the normally rigorous dosing regimen used for aldesleukin (a non-pegylated recombinant IL-2), and as a result a lower effective dose and less frequent required administration would be expected. Support for this comes from the PIVOT-02 trial, taught by Diab, which comprised the administration of bempegaldesleukin, a pegylated variant of aldesleukin, and used recommended phase II dose of 6 μg/kg, administered every three weeks to patients with advanced solid tumors, such as melanoma, renal cell, carcinoma, and non-small cell lung cancer (relevant to instant claims 44, 47, 53, and 62) (Abstract). Despite the differences between the bioconjugated IL-2 disclosed in the current application and bempegaldesleukin, the two therapeutics share an increased serum half-life, relative to aldesleukin, due to the attachment of PEG polymer(s), and as such the dosing regimen, taught by Diab, would have been an obvious starting point for routine optimization. MPEP 2144.05 (II) speaks to Routine Optimization stating that "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and ‘It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.’ In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929)). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”. The limitations established in instant claims 1-4, 70-73, and 75-77, regarding dosing regimen, would have been obvious following routine optimization, using the initial guidance provided by Diab, for the various forms of immune-reactive cancers, to which the current invention is intended to be applied.
In regard to claim 15, Ptacin teaches pharmaceutical compositions comprising IL-2 conjugates and pharmaceutically acceptable excipients ([0010]).
Claims 50 and 51 are rejected are rejected under 35 U.S.C. 103 as being unpatentable over WO2019028425 A1 (herein Ptacin), Tang A, Harding F. (2019) The challenges and molecular approaches surrounding interleukin-2-based therapeutics in cancer. Cytokine X. 2018 Dec 10;1(1):100001 (herein Tang) and Stauber DJ, et al. (2006) Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2788-93 (herein Stauber), in view of in Meloni G, et al. (1997) Interleukin-2 therapy in relapsed acute myelogenous leukemia. Cancer J Sci Am. 1997 Dec;3 Suppl 1:S43-7 (herein Meloni), with Diab A, et al. (2020) Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). Cancer Discov. 2020 Aug;10(8):1158-1173 (herein Diab) and Ramil CP, Lin Q. (2013) Bioorthogonal chemistry: strategies and recent developments. Chem Commun (Camb). 2013 Dec 7;49(94):11007-22 (herein Ramil) providing additional evidentiary value.
Ptacin, Tang, and Steuber teach a method for treating an immune-reactive cancer in a human subject comprising the administration of an IL-2-bioconjugate, as discussed for the 103 rejections of claims 1-4, 13-15, 17, 19, 37, 44, 47, 58, 62, and 70-77. Ptacin, Tang, and Steuber do not explicitly teach the use of bioconjugated-IL2 for use in treating relapsed or refractory cancer (although prior art does teach the use of aldesleukin for such cases). Ptacin, Tang, and Steuber also do not teach the use of an IL-2 bioconjugate for the treatment of a liquid tumor. Meloni teaches these deficiencies.
Meloni et al summarize pilot studies assessing the activity of recombinant IL-2 in patients with relapsed-refractory acute myelogenous leukemia (AML) and in second complete remission, who are not eligible for standard therapy (Purpose). In the pilot study, 13 patients (54%) obtained a complete remission, which persists in eight patients with a median follow-up of 64 months (range, 1-110 months) on maintenance rIL-2 (Results). In the randomized study, a trend in favor of improved disease-free survival was observed in the rIL-2 arm (Results).
This study provides motivation to direct the method taught by Ptacin, Tang, and Steuber towards the treatment of relapsed-refractory AML, characterized by liquid tumors, as Meloni et demonstrate that recombinant IL-2 showed encouraging results for treating patients suffering from refractory or relapsed forms of the disease. It would have been obvious to one skilled in the art, at the time of filing, to combine the IL-2 bioconjugate, taught by Ptacin, Tang, and Steuber, with method taught by Meloni, as the applicant is substituting one element (recombinant IL-2) with a second element (IL-2 bioconjugate) that performs the same function. Despite the fact that the IL-2 bioconjugate possesses superior pharmacological properties, the combination remains obvious, as the superior properties (i.e. reduced IL-2Rα affinity and increased serum half-life) are retained in the resulting methods and behave in a predictable manner.
Claim 53 is rejected under rejected 35 U.S.C. 103 as being unpatentable over WO2019028425 A1 (herein Ptacin), Tang A, Harding F. (2019) The challenges and molecular approaches surrounding interleukin-2-based therapeutics in cancer. Cytokine X. 2018 Dec 10;1(1):100001 (herein Tang) and Stauber DJ, et al. (2006) Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2788-93 (herein Stauber), in view of Zhang X, et al. (2015) The functional and prognostic implications of regulatory T cells in colorectal carcinoma. J Gastrointest Oncol. 2015 Jun;6(3):307-13 (herein Zhang), with Diab A, et al. (2020) Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). Cancer Discov. 2020 Aug;10(8):1158-1173 (herein Diab) and Ramil CP, Lin Q. (2013) Bioorthogonal chemistry: strategies and recent developments. Chem Commun (Camb). 2013 Dec 7;49(94):11007-22 (herein Ramil) providing additional evidentiary value.
Ptacin, Tang, and Steuber teach a method for treating an immune-reactive cancer in a human subject comprising the administration of an IL-2-bioconjugate, as discussed for the 103 rejections of claims 1-4, 13-15, 17, 19, 37, 44, 47, 58, 62, and 70-77. Ptacin, Tang, and Steuber do not explicitly teach the use of bioconjugated-IL2 for use in treating colorectal cancer (selected by the applicant following an election of species request). Zhang teaches this deficiency.
Zhang et al provide a literature review summarizing the functional and prognostic implications of Treg cell in colorectal carcinoma (Abstract). Zhang teaches that Treg cells have received considerable attention in the field of immunology, due to their role in promoting immunosuppressive tumor microenvironments in various cancers (paragraph 1 of Section: The Function of Tregs in CRC is Controversial). Zhang also teaches that the role of Tregs in tumor immunity was first discovered when anti-tumor T cell immune responses in mice were enhanced following Treg inhibition, via an anti-CD25 (anti-IL-2Rα) antibody (paragraph 2 of Section: The Function of Tregs in CRC is Controversial). Zhang teaches that colorectal carcinoma patients show elevated levels of Tregs in circulation, draining lymph nodes, and most importantly at tumor sites (Figure 1 and Section: Tregs are Increased and Enriched in Colorectal Cancer Patients). In this same section, it is taught that the elimination and/or functional inactivation of tumor-induced Tregs can increase immunotherapy efficacy in a rat colon cancer model. Zhang does note that there still exists controversy surrounding whether or not the abundance of Treg cells at the tumor site is hazard or benefit, regarding the progression of colorectal cancer, but it is made clear that Treg-mediated immunosuppression is a crucial mechanism in tumor-immune evasion (Section: Potential Therapeutic Strategies for CRC).
When considering the teachings of Zhang the application of the method, taught by Ptacin, Tang, and Stauber, towards colorectal cancer would have been obvious to one skilled in the art, at the time of filing. As taught by Zhang, colorectal cancer tumors have elevated Treg concentrations, which contributes to suppression of Teff and NK cell activation (Figure 1 and Section: Tregs are Increased and Enriched in Colorectal Cancer Patients and Section: Treg Introduction). The administration of an IL-2 molecule that does not compete with the high affinity IL-2R would allow for circumvention of the immunosuppressive tumor microenvironment, while preserving the Treg population, which Zhang teaches may or may not be beneficial to the patient.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 13-15, 17, 19, 37, 44, 47, 50-51, 53, 58, 62 and 70-77 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-34, 37, 38, 40-42, 46-51 of U.S. Patent No. 11077195 (herein ‘195) in view of WO2019028425 A1 (herein Ptacin), Tang A, Harding F. (2019) The challenges and molecular approaches surrounding interleukin-2-based therapeutics in cancer. Cytokine X. 2018 Dec 10;1(1):100001 (herein Tang) and Stauber DJ, et al. (2006) Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2788-93 (herein Stauber), in view of Zhang X, et al. (2015) The functional and prognostic implications of regulatory T cells in colorectal carcinoma. J Gastrointest Oncol. 2015 Jun;6(3):307-13 (herein Zhang), with Diab A, et al. (2020) Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). Cancer Discov. 2020 Aug;10(8):1158-1173 (herein Diab) and Ramil CP, Lin Q. (2013) Bioorthogonal chemistry: strategies and recent developments. Chem Commun (Camb). 2013 Dec 7;49(94):11007-22 (herein Ramil) providing additional evidentiary value.
Although the claims at issue are not identical, they are not patentably distinct from each other, because they describe an IL-2 bioconjugate, that shares the structural limitations as that described in the instant application. ‘195 does not teach a method for using the IL-2 conjugate described in the referenced claims, but as detailed in the 35 U.S.C. 103 rejections of the current application, the prior art teaches a method of using the described bioconjugate as a treating immune-reactive cancer. Regarding the limitation of treatment of cancer, claim 1, Tang teaches that IL-2 can be used to treat cancer (Abstract and Section 2 paragraph 5). Regarding the limitations involving dosage, Diab teaches a starting point from which routine optimization would render the limitations of the instant claims 1-4, 44, 70-73, and 75-77 obvious (Abstract).
Claims 1-4, 13-15, 17, 19, 37, 44, 47, 50-51, 53, 58, 62 and 70-77 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 30, and 31 of U.S. Patent No. 10610571 (herein ‘571) in view of WO2019028425 A1 (herein Ptacin), Tang A, Harding F. (2019) The challenges and molecular approaches surrounding interleukin-2-based therapeutics in cancer. Cytokine X. 2018 Dec 10;1(1):100001 (herein Tang) and Stauber DJ, et al. (2006) Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2788-93 (herein Stauber), in view of Zhang X, et al. (2015) The functional and prognostic implications of regulatory T cells in colorectal carcinoma. J Gastrointest Oncol. 2015 Jun;6(3):307-13 (herein Zhang), with Diab A, et al. (2020) Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). Cancer Discov. 2020 Aug;10(8):1158-1173 (herein Diab) and Ramil CP, Lin Q. (2013) Bioorthogonal chemistry: strategies and recent developments. Chem Commun (Camb). 2013 Dec 7;49(94):11007-22 (herein Ramil) providing additional evidentiary value.
Although the claims at issue are not identical, they are not patentably distinct from each other, because the referenced claims effectively encompass the composition of the IL-2 conjugate described in the current application. ‘571 does not teach all of the limitations established in the instant claims regarding the nature/position of the unnatural amino acid or the conjugating moiety, nor does it teach the method for using the IL-2 conjugate described in the referenced claims, but as detailed in the 35 U.S.C. 103 rejections of the current application, the prior art teaches the limitations regarding the nature/position of the unnatural amino acid, the conjugating moiety, and the method of using the described bioconjugate as a treating immune-reactive cancer. Regarding the limitation of treatment of cancer, Tang teaches that IL-2 can be used to treat cancer (Abstract and Section 2 paragraph 5). Regarding the limitations involving dosage, Diab teaches a starting point from which routine optimization would render the limitations of the instant claims 1-4, 44, 70-73, and 75-77 to be obvious (Abstract). Regarding the limitations referencing selection of P65 (all instant claims) (P64 in the current application) as the site of modification, Stauber teaches the selection corresponding to this position, based on its position within the hydrophobic center of the IL-2-IL-2Rα interface relevant to instant claims (Results: Structure of IL-2Rα and Its Interface with IL-2). Regarding the structure of the water-soluble polymeric moiety and linker, Ptacin teaches the structure corresponding to Formula 1A, XII, XIII, IVA, XIIA, XIIIA, and VA. The unnatural amino acid(s) is/are taught to comprise a reactive group for chemistry used in site-selective biorthogonal reactions (i.e. copper-free alkyne-azole triazole-forming reactions) ([0077]). Embodiments, in which the conjugation reaction comprises a reaction between an azide and a strained alkyne, are taught ([0185]). It is also taught that the azide group may be contained on the unnatural amino acid and that the unnatural amino may be N6-azidoehthoxy-L-lysine (AzK) (relevant to instant claim 14) ([0005-0006] and claim 14), and that the strained alkyne may be a cycloalkyne ([0185]). The conjugating moiety is taught to contain a water-soluble polymer, which may comprise polyethylene glycol (PEG), and may be capped, as exemplified by mPEG ([0005], [0127], and claims 18 and 19). Several exemplary pegylated IL-2 compound are disclosed, comprising IL-2 conjugated to moieties comprising a water-soluble polymer with an approximate molecular weight of 30 kDa (relevant to instant claim 13) (Table 2, [0316]). In regard to the structure of the linker, referenced as either Z or Y in claim 1, the disclosed structures would have been the result of reactions, aimed at producing a PEG reagent suitable for use in SPAAC (DBCO-mPEG), using widely available commercial products (e.g. DBCO-amine or DBCO-acid reacted with carboxylic-terminated PEG or amine-terminated PEG, respectively, with the appropriate activating agents, and illustrated below), that would have been obvious and routine to one skilled in the art, at the time of filing. This reagent would result in a q value of one in relation to instant claims 1, 14, 17, 19, and 37.
Claims 1-4, 13-15, 17, 19, 37, 44, 47, 50-51, 53, 58, 62 and 70-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 4-7, 10-15, 18, 21, 22, 24, 29, 34, 35, 41, and 42 of copending Application No. 18296710 (herein ‘710). Although the claims at issue are not identical, they are not patentably distinct from each other, because all the claims within ‘710 encompass the invention described in the current application. The referenced claims within ‘710 are nearly identical to those of the current application, with the exception that instant claims do not include limitations that integrate pembrolizumab, but the claims of the instant application make use of the term “comprise”, which would allow for the inclusion of pembrolizumab.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4, 13-15, 17, 19, 37, 44, 47, 50-51, 53, 58, 62 and 70-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 3, 5, 6, 9, 10, 11, 12, 13, 14, 18, 24, 25, 28, 30, 36, and 38 of copending Application No. 18447808 (herein ‘808). Although the claims at issue are not identical, they are not patentably distinct from each other, because all the claims within ‘808 encompass the invention described in the current application. The referenced claims within ‘808 are nearly identical to those of the current application, with the exception that the instant claims do not include limitations that integrate an anti-PD-1 antibody, but the claims of the instant application make use of the term “comprise”, which would allow for the inclusion of an anti-PD-1 antibody.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4, 13-15, 17, 19, 37, 44, 47, 50-51, 53, 58, 62 and 70-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 9, 11-14, 17, 19-21, 26, 28, 34, and 36 of copending Application No. 18524157 (herein ‘157). Although the claims at issue are not identical, they are not patentably distinct from each other, because all the claims within ‘157 encompass the invention described in the current application. The referenced claims within ‘157 are nearly identical to those of the current application, with the exception that the instant claims do not include limitations that integrate cetuximab, but the claims of the instant application make use of the term “comprise”, which would allow for the inclusion of cetuximab.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4, 13-15, 17, 19, 37, 44, 47, 50-51, 53, 58, 62 and 70-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-8, 14, 15, 18, 21, and 29 of copending Application No. 18722300 (herein ‘300). Although the claims at issue are not identical, they are not patentably distinct from each other, because all the claims within ‘300 encompass the invention described in the current application. The referenced claims within ‘300 are nearly identical to those of the current application, with the exception that the instant claims do not include limitations that integrate an anti-PD-1 antibody, but the claims of the instant application make use of the term “comprise”, which would allow for the inclusion of an anti-PD-1 antibody.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
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/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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