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 .
DETAILED ACTION
The preliminary amendment dated 24 June 2024, in which claims 4, 9, 12, 15-16, 19, 20, 27, 30, 36, 41, 44 have been amended, and claims 5-8, 11, 14, 17-18, 21-26, 28-29, 32, 34-35, 37-40, 42-43, 45-61 have been cancelled, is acknowledged.
Claims 1-4, 9-10, 12-13, 15-16, 19-20, 27, 30-31, 33, 36, 41, 44 are pending in the instant application.
Claims 12, 13, 15, 33, 36, 41, 44 are withdrawn as being drawn to a nonelected invention or to a non-elected species.
Claims 1-4, 9-10, 16, 19-20, 27, 30-31 are being examined on their merits herein.
Priority
This application is a 371 of International Application PCT/US2022/029267, filed on 13 May 2022, which claims the benefit of U.S. Provisional Patent Application 63/188,892, filed on 14 May 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 13 November 2023 and 10 June 2026 are acknowledged and considered.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-4, 9-10, 12-13, 15-16, 19-20, 27, 30-31, drawn to a conjugate of formula I: EVTsmL-L-AMRL (formula I) wherein EVTsmL is a radical of an enveloped virus-targeting, small molecule ligand, AMRL is a radical of an activated macrophage-recruiting ligand, and L is a linker that is covalently bound to EVTsmL and AMRL, or a pharmaceutically acceptable salt thereof, in the reply filed on 21 July 2026, is acknowledged. Claims 33, 36, 41, 44 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Applicants’ election without traverse of compound Formula II (Specification, [00018]) below:
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as the species of a conjugate of formula I: EVTsmL-L-AMRL, for initial examination, in the reply filed on 21 July 2026, is acknowledged. The examiner notes that the elected species compound Formula II (also called ZAN-PEG6-Fol, compound 10, Example 1, Specification) is a compound of formula (I) EVTsmL-L-AMRL to which the following definitions apply: EVTsmL is zanamivir, AMRL is folate (pteroylmonoglutamate), and the linker L comprises PEG6.
Claims 1-4, 9-10, 16, 19-20, 27, 30-31 read on the elected species. Claims 12, 13, 15 are withdrawn, as being drawn to a non-elected species.
Since Applicant has set forth no arguments against the requirement for restriction, it is considered that the election was made without traverse, and the restriction requirement is maintained and is herein made FINAL.
Claims 1-4, 9-10, 16, 19-20, 27, 30-31 have been examined to the extent they read on the elected species: compound Formula II, and the following rejections and objections are made below.
Claim Objection
Claims 12, 13, 15, while currently withdrawn, are objected to because of the following informality: they are presented in a non-compliant form. Specifically, the status identifiers for claims 12, 13, 15 should read "(Withdrawn)" until such time as examiner rejoins the claims for examination. Appropriate correction is required. See MPEP 714(C).
Claims Rejection
Claims 1-3, 9-10, 16, 19-20, 30-31 are rejected on the judicially-created basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: the species of the Markush group do not share a "single structural similarity." Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class.
The instant claim does not share a common core chemical structure or single structural similarity. The instant claim is drawn to a compound of formula (I): EVTsmL-L-AMRL (formula I) wherein EVTsmL is a radical of an enveloped virus-targeting, small molecule ligand, AMRL is a radical of an activated macrophage-recruiting ligand, and L is a linker that is covalently bound to EVTsmL and AMRL.
The conjugates in claim 1, used to treat infections with an enveloped virus, such as influenza, correspond to any (structurally distinct) small molecules that target an enveloped virus, which are connected by Linker, which is any linking group, to any AMRL. There is a great structural variety for the broadly claimed EVTsmL, broadly claimed linkers, in combination with the broadly claimed AMRLs.
Each combination of elements EVTsmL, linker, AMRL requires different structural search and/or a different classification based on its structural elements. In addition, these species are not obvious variants of each other based on the current record.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature, such as, for example, a compound of formula (I) where EVTsmL is one of the antiviral agents in instant claim 4, connected via linker(s) having a specific structure to AMRL having a distinct chemical structure.
This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1).
Thus, for the reasons discussed above, claims 1-3, 9-10, 16, 19-20, 30-31 are rejected.
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 for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-4, 9-10, 16, 19-20, 27, 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Liu, Xin (Small molecule ligand-targeted delivery of therapeutic agents for treatment of influenza virus infection, Ph.D. Dissertation, Purdue University, May 2020, cited in PTO-892), in view of Vlahov et al. (US 7,601,332, cited in PTO-892), in further view of Han et al. (Am J Respir Cell Mol Biol 2015, 53 (1) 50-59, cited in PTO-892).
Liu teaches (Chapter 2, page 26, last paragraph) that zanamivir, which is an EVTsmL of instant claim 4, is a neuraminidase inhibitor, as in instant claim 3, and an anti-influenza drug approved by the US FDA.
Liu teaches (Figure 2.1 B) zanamivir-targeted drug conjugates synthesized by conjugating zanamivir (targeting ligand) with the paylod via a PEG chain (linker).
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Liu teaches (Scheme 2.1) the synthesis of zanamivir-related influenza neuraminidase targeting ligand
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, where zanamivir is linked to a payload through a hydrophilic linker PEG, as in instant claims 9, 10, via a carbamate bond at the C7-hydroxyl position of zanamivir, as in the instant elected species (claim 27).
Liu teaches that the C7-hydroxyl position of zanamivir tolerates derivatization with bulky linkers without compromising inhibitory potency or binding affinity against influenza virus neuraminidase (page 27, first paragraph).
Liu teaches (page 27) the synthesis of two zanamivir-targeted imaging conjugates, zanamivir rhodamine conjugate (zan-rhodamine) and zanamivir-99mTc peptide chelator conjugate (zan 99mTc).
Liu teaches (page 28, last 3 lines) that zanamivir -related targeting ligand can be used as a targeting ligand to deliver therapeutic and imaging agents to influenza virus and virus-infected cells.
Liu does not teach a zanamivir conjugate where the “payload” is folate or pteroyl glutamine, as in instant claims 16, 19, 20, 27.
Vlahov et al. (US 7,601,332) teach vitamin receptor binding drug conjugates V-L-D, where V is a vitamin, L is a linker, D is a drug, where the vitamin is, for example, folate or a derivative thereof, and the drug is, for example, an antiviral agent.
Vlahov teaches (column 49) vitamins or derivatives thereof used in the drug conjugates of the invention include those that bind to receptors specifically on activated macrophages, such as the folate receptor which binds folate or an analog thereof.
The folate-linked conjugates can be used to kill or suppress the activity of activated macrophages that cause disease states in the host. Such macrophage targeting conjugates, when administered to a patient suffering from an activated macrophage-mediated disease state, work to concentrate and associate the conjugated drug in the population of activated macrophages to kill the activated macrophages or suppress macrophage function. Elimination, reduction, or deactivation of the activated macrophage population works to stop or reduce the activated macrophage-mediated pathogenesis characteristic of the disease state being treated.
The invention is applicable to populations of pathogenic cells that cause a variety of pathologies in these host animals. In accordance with the invention "pathogenic cells" means cancer cells, infectious agents such as viruses, virus-infected cells, activated macrophages capable of causing a disease state, and any other type of pathogenic cells that uniquely express, preferentially express, or overexpress vitamin receptors or receptors that bind analogs or derivatives of vitamins.
Han et al. (Am J Respir Cell Mol Biol 2015, 53 (1) 50-59, cited in PTO-892) teach (page 51, left column , second paragraph) that macrophage specific folate receptor beta FRbeta expression has been documented in several inflammatory diseases, including rheumatoid arthritis, osteoarthritis, lupus, cancer. Han teaches that during lung inflammation, FRbeta expression is upregulated in interstitial macrophages. Han employs a fluorophore-conjugated folate derivative to demonstrate that folate uptake via FRbeta is a robust target for molecular imaging of macrophage activation during acute lung inflammation (page 52, first paragraph).
It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Liu, Vlahov and Han to arrive at the instant invention. A person of ordinary skill in the art at the time the invention was made would have been motivated to synthesize a zanamivir conjugate where the “payload” is folate or pteroyl glutamine, because
Liu teaches zanamivir conjugate drugs where zanamivir is linked to a payload through a hydrophilic linker PEG, via a carbamate bond at the C7-hydroxyl position of zanamivir,
without compromising inhibitory potency or binding affinity against influenza virus neuraminidase,
Liu teaches that zanamivir -related targeting ligand can be used as a targeting ligand to deliver therapeutic agents to influenza virus and virus-infected cells;
Vlahov et al. (US 7,601,332) teach vitamin receptor binding drug conjugates V-L-D, where V is a vitamin, L is a linker, D is a drug, where the vitamin is, for example, folate or a derivative thereof, and the drug is, for example, an antiviral agent.
Vlahov teaches folate-linked conjugates used to kill or suppress the activity of activated macrophages that cause disease states in the host, applicable to pathogenic cells such as
virus-infected cells that overexpress folate receptors;
and Han teaches that macrophage specific folate receptor beta FRbeta expression is upregulated in activated macrophages in acute lung inflammation.
Thus, a person of ordinary skill in the art would have prepared a zanamivir conjugate drug by linking the zanamivir to a payload through a hydrophilic linker PEG, via a carbamate bond at the C7-hydroxyl position of zanamivir, where the “payload” is folate or pteroyl glutamine folate, with the expectation that the resulting drug conjugate retains the neuraminidase binding affinity of zanamivir, and the folate-PEG conjugate readily binds the FR-beta of the macrophages to induce viral phagocytosis and immune clearance.
As such, claims 1-4, 9-10, 16, 19-20, 27, 30-31 are rejected as prima facie obvious.
Conclusion
Claims 1-4, 9-10, 16, 19-20, 27, 30-31 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY S. LUNDGREN can be reached at (571)272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/IRINA NEAGU/Primary Examiner, Art Unit 1629
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