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 .
Election/Restrictions
Applicant's election with traverse of Group II, specie 47-122 in the reply filed on 30 July 2026 is acknowledged. The traversal is on the ground(s) that the search would not be burdensome. This is not found persuasive because the numerous variations possible for formula A are incalculable. This search would be a burden on the examiner and office. The requirement is still deemed proper and is therefore made FINAL.
Claims 2, 4-7, 10, 12-14, 16 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention. Applicant timely traversed the restriction (election) requirement in the reply filed on 30 July 2026.
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.
Claims 1, 3, 8, 9, 11, and 15 is/are rejected under 35 U.S.C. § 103 as being unpatentable over Yuan et al., (WO 2017/198124), in view of Ashley et al., (WO 2015/051307), and further in view of WO 2019/096096.
Yuan et al. disclose a targeted multi-branched drug conjugate having three or more branches, wherein R is an organic center, POLY is a polymer, and POLY and X together form a polymer branch. Yuan further disclose that the organic center R may emit at least three independent polymer branches, with q corresponding to the number of polymer branches from R. See Yuan, lines 531–543. Yuan also teach that the multi-branched conjugate may include a multivalent linker L, a targeting molecule T, and an active agent D, wherein POLY, T, and D are joined through the multivalent linker. See Yuan, lines 600–607 and 612–617.
Yuan teach that the active agent D may be a camptothecin anticancer agent and preferably may be irinotecan, SN-38, 10-hydroxycamptothecin, or rubitecan. Yuan expressly identify SN-38 as one of the preferred active agents. See Yuan, lines 643–653. Yuan further teach that the targeting molecule T increases targeting so that the conjugate concentration in target tissue is higher, and that T may be an RGD peptide, iRGD, cRGD, tLyp-1, Lyp-1, RPARPAR, Angiopep2, GE11, or folic acid. See Yuan, lines 656–672.
Yuan also teach multi-arm PEG embodiments. Specifically, Yuan disclose that POLY may be a polyethylene glycol linking arm and identify three-arm, four-arm, and eight-arm PEG embodiments. See Yuan, lines 673–679. Yuan further disclose that, in a preferred embodiment, the targeting moiety T is selected from iRGD, tLyp-1, Lyp-1, RPARPAR, cRGD, Angiopep2, GE11, or folic acid, and the active agent D is selected from irinotecan, SN-38, 10-hydroxycamptothecin, or rubitecan. See Yuan, lines 693–694. Yuan additionally disclose that commercially available multi-arm PEGs may be directly reacted with the D-L portion, including 4armPEG20K-SCM, 3armPEG20K-SCM, and 8armPEG20K-SCM. See Yuan, lines 888–903.
Ashley et al. disclose PEG-SN38 conjugates. Ashley teach conjugates of formula (I), wherein PEG is a polyethylene glycol of average molecular weight between 20,000 and 60,000 Da, which may be linear or branched and, when q is 2–8, multi-armed. See Ashley, ¶ [0008], lines 323–327. Ashley further teach that PEG may be linear or branched and, when q is 2–8, multi-armed polyethylene glycol, with q = 1–8. See Ashley, ¶ [0021], lines 356–366. Ashley also disclose a 4-arm PEG-SN38 conjugate, wherein q = 4, PEG is a 4-arm polyethylene glycol having a pentaerythritol core, and the PEG has an average molecular weight of 40,000. See Ashley, ¶¶ [0016]–[0020], lines 348–354.
Ashley further teach that the PEG may be a 4-arm polymer having a pentaerythritol core and an average molecular weight of 40,000 ± 4,000 Da, with each arm terminated by a carboxylate group. See Ashley, ¶ [0031], lines 413–416. Ashley also claim PEG-SN38 conjugates wherein PEG is linear or branched and, when q is 2–8, multi-armed; q may be 4; and the conjugate may include multi-armed PEG having an average molecular weight of 30,000–50,000 Da. See Ashley, claims 1, 4, and 6, lines 668–690.
Ashley teach preparation of PEG-SN38 conjugates by reducing an azide-linker-SN38 to an amino-linker-SN38 and contacting the amino-linker-SN38 with activated PEG to produce the conjugate. See Ashley, claim 11, lines 701–706. Ashley also teach that amine-linker-SN38 may be connected to activated PEG, and that carboxy-terminated PEG may be coupled using peptide coupling agents such as DCC, EDCI, BOP, PyBOP, HATU, or HBTU in solvents such as acetonitrile, THF, DMF, or dichloromethane. See Ashley, ¶ [0039], lines 439–444. Ashley further teach purification of the resulting conjugates by precipitation, dialysis, or size-exclusion chromatography. See Ashley, ¶ [0040], lines 446–447.
WO 2019/096096 A1 further supports the targeting rationale. WO 2019/096096 teaches that folate receptor is a membrane glycoprotein and that folic acid can specifically bind to folate receptors. It further teaches that adding folic acid to the complex allows uptake by receptor-mediated endocytosis and provides a specific targeted drug-delivery route for folate-receptor-positive tumor cells. See WO 2019/096096, lines 101–102. WO 2019/096096 also teaches targeted multi-arm drug conjugates in which a branch includes polymer POLY, multivalent linker L, targeting molecule T, and active agent D, with POLY being polyethylene glycol. See WO 2019/096096, lines 103–108. The reference further teaches that water-soluble polymer modification enhances water solubility and increases drug loading, and that folic acid actively targets folate-receptor-rich tumor cells. See WO 2019/096096, lines 116–121.
It would have been obvious to one of ordinary skill in the art before the effective filing date to prepare a Formula II multi-arm PEG anticancer conjugate within the scope of claims 1 and 3 by combining the multi-arm targeted polymer conjugate platform of Yuan with the PEG-SN38 conjugate teachings of Ashley and the folate-targeting rationale of WO 2019/096096. Yuan teaches the overall targeted multi-arm polymer anticancer conjugate framework, including multi-arm PEG, a multivalent linker, targeting molecules including folic acid and peptide targeting groups, and active agents including SN-38. Ashley teaches the specific use of multi-arm PEG-SN38 conjugates, including q = 4, 4-arm PEG, activated PEG coupling chemistry, and pharmaceutical formulations. WO 2019/096096 provides additional motivation to use folic acid targeting because folic acid binds folate receptors and supports receptor-mediated uptake by folate-receptor-positive tumor cells.
The motivation to combine would have been to obtain a targeted multi-arm PEG/polymer anticancer conjugate having improved aqueous solubility, increased drug loading, controlled release of an SN-38/camptothecin-type anticancer payload, and targeted delivery to tumor cells. The expectation of success would have been reasonable because each reference is directed to the same field of polymer/PEG anticancer drug conjugates and teaches the same functional components: multi-arm PEG/polymer carrier, multivalent linker, camptothecin/SN-38-type active agent, and peptide or folate targeting.
As to claim 1, Yuan teaches a PEG/polymer multi-branched targeted anticancer conjugate having an organic center, polymer arms, multivalent linker, targeting molecule, and active agent. See Yuan, lines 531–543 and 600–607. Yuan teaches SN-38 as a preferred active agent and folic acid/peptide targeting molecules as targeting groups. See Yuan, lines 643–653 and 656–672. Ashley teaches multi-arm PEG-SN38 conjugates, including q = 4 and PEG of 20,000–60,000 Da. See Ashley, ¶ [0021], lines 356–366. Thus, the cited art renders obvious the broadly recited PEG conjugated drug of claim 1.
As to claim 3, the claim is directed to the Formula II species, including PEGm/multi-arm PEG features. Yuan teaches multi-arm PEG embodiments, including three-arm, four-arm, and eight-arm PEG structures. See Yuan, lines 673–679. Yuan further teaches commercially available multi-arm PEG derivatives, including 4armPEG20K-SCM. See Yuan, lines 888–903. Ashley teaches q = 4, 4-arm PEG-SN38 conjugates, and a 4-arm PEG having a pentaerythritol core and average molecular weight of 40,000. See Ashley, ¶¶ [0016]–[0020], lines 348–354, and ¶ [0031], lines 413–416. Accordingly, the Formula II multi-arm PEG species would have been obvious.
As to claim 8, including elected compound 47-122, the specification identifies compound 47-122 and reports that product 47-122 was obtained in 1.09 g with an 84% yield. See WO2022022360A1, lines 2643–2645. The prior art does not expressly disclose the exact compound 47-122. However, claim 8 is rendered obvious because the elected species represents the predictable use of known multi-arm PEG, known SN-38/camptothecin payloads, known multivalent linker chemistry, known activated PEG/amino-linker coupling chemistry, and known folate/peptide targeting in the same anticancer PEG-conjugate field.
As to claim 9, the claim is directed to intermediates useful for preparing the PEG conjugated drugs of claims 1–8. The specification describes intermediates bearing amino and carboxyl functionality for preparing the PEG conjugated drug. See WO2022022360A1, lines 1869–1888. Ashley teaches azide-linker-SN38 and amino-linker-SN38 intermediates, and teaches contacting amino-linker-SN38 with activated PEG to produce the conjugate. See Ashley, ¶¶ [0014]–[0016], lines 345–348, and claim 11, lines 701–706. Ashley further teaches carboxy-terminated PEG coupling with peptide-coupling agents such as DCC, EDCI, BOP, PyBOP, HATU, or HBTU in acetonitrile, THF, DMF, or dichloromethane. See Ashley, ¶ [0039], lines 439–444. Therefore, the intermediates corresponding to the elected Formula II/47-122 pathway would have been obvious as routine intermediates for preparing the otherwise obvious conjugate.
As to claim 11, the claim recites preparation of the Formula II conjugate through intermediates and amidation chemistry. The specification describes use of PEG having a carboxyl or activated carboxyl group and amidation reactions to obtain the PEG conjugated drug. See WO2022022360A1, lines 1877–1888. Ashley teaches the same type of activated PEG/amino-linker coupling and carboxy-terminated PEG coupling chemistry using HATU/HBTU-type coupling agents in conventional organic solvents. See Ashley, ¶ [0039], lines 439–444. Thus, the preparation method would have been obvious as the routine preparation of an otherwise obvious multi-arm PEG-SN38 conjugate.
As to claim 15, the claim recites a pharmaceutical composition comprising the PEG conjugated drug of claims 1–8 or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients. The specification describes pharmaceutical compositions containing the PEG conjugated drug and one or more pharmaceutically acceptable adjuvants, carriers, or excipients. See WO2022022360A1, lines 1952–1957. Ashley expressly claims a pharmaceutical formulation comprising a conjugate of claims 1–8 together with a pharmaceutically acceptable excipient. See Ashley, claim 9, lines 697–699. Claim 15 is therefore obvious over the cited combination.
Claim Rejections - 35 USC § 112
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, 3, 8-9, 11, 15 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, the claims recites the broad recitation “preferably” throughout the claims, and the claim also recites the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DEBORAH D CARR whose telephone number is (571)272-0637. The examiner can normally be reached Monday-Friday (10:30 am -6:30 pm).
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/DEBORAH D CARR/Primary Examiner, Art Unit 1691
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