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 .
Claim 2 has been canceled. Claims 1, 5, 6, 8, 11-13, 16, 18-20, 22-24, 27-31, 37-40, 42, 44, 45, 50 and 51 are pending and under consideration to the extent that they encompass the elected species of P-III and P-IV.
As stated in the prior action, The provisional application provides a written description of the exatecan derivatives P-I and P-II but fails to provide any written description of the instant camptothecin derivatives P-III and P-IV. Thus, benefit of earlier priority is not extended to the instant claims requiring the camptothecin derivatives P-III and P-IV. The claims will be considered to have the priority date of 1/10/2023.
The rejection of claim 28 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph for lacking definitions for the “R” substituents is withdrawn in light of applicant’s amendments.
The rejection of claims 44 and 45 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph for lacking any active, positive steps that define the claimed method is withdrawn in light of applicant’s amendments.
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.
Claim 18 is 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)Claim 18 is vague and indefinite in the case wherein SP2 is absent. It is unclear if the “second spacer unit” is covalently attached to the “P”
(B)Further, it is unclear how SP2 differs from the second linker because neither claim 18, nor claim 1 define SP2 and by the same token, it is unclear how SP1 differs from the second linker because neither claim 18, nor claim 1 define SP1.
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.
The rejection of claims 50 and 51 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of making a triazole comprising the cycloaddition of azide to
PNG
media_image1.png
66
146
media_image1.png
Greyscale
or
PNG
media_image2.png
64
58
media_image2.png
Greyscale
, does not reasonably provide enablement for the cycloaddition of tetrazine to
PNG
media_image1.png
66
146
media_image1.png
Greyscale
or
PNG
media_image2.png
64
58
media_image2.png
Greyscale
. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims is maintained for reasons of record..
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re wands, 858 F.2d 731, 737.8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 50 is directed in part to the use of ,
PNG
media_image3.png
50
63
media_image3.png
Greyscale
, as opposed to N3, in the formation of a triazole when paired with
PNG
media_image4.png
85
224
media_image4.png
Greyscale
The art teaches the well-known Huisgen 1,3-dipolar cycloaddition of azido and alkynes to yield triazoles
PNG
media_image5.png
116
336
media_image5.png
Greyscale
(Gil et al, Synthesis, 2007, No. 11, pp. 1589-1620, see page 1594). However, the art teaches that tetrazines and alkynes undergo cycloaddition to extrude N2 producing an addition product which is not a triazole
PNG
media_image6.png
197
360
media_image6.png
Greyscale
(Chen et al, Chemical Communications, 2012, Vol. 48, pp. 1736-1738, see Figure 1, A and B on page 1737, cited in the prior Action). The specification fails to provide and teachings or guidance for forming a triazole from a tetrazine and an alkyne. Thus, one of skill in art would be subject to undue experimentation in order to carry out the broadly claimed method of producing the compound BA-(L1-B-L2-P) using a reaction between an alkyne and a tetrazine wherein B was a triazole.
Claim 51 is included with this rejection to the extent that the compound s a compound of Formula (A).
Applicant argues that the specification is enabling for the cycloaddition of tetrazine to alkynes and cites pages 12, 25, 26, 74-76 and 158-161. This has been considered but not found persuasive. Claims 50 specifically requires:
PNG
media_image7.png
73
511
media_image7.png
Greyscale
PNG
media_image8.png
24
213
media_image8.png
Greyscale
A triazole is a 5-atom ring, having 2 carbons and 3 nitrogens. It is noted that although pages12, 25, 26, 74-76 and 158-161, illustrate the products of a cycloaddition between an octyne and a tetrazine, the resulting products are not triazoles because they are 6-atoms rings having 4 carbons and two nitrogen. For example, on page 25:
PNG
media_image9.png
182
546
media_image9.png
Greyscale
Applicant’s argument is moot.
The rejection of claims 37 and 39 under 35 U.S.C. 102(a)(1) as being anticipated by Adams et al (Cancer Chemotherapy and Pharmacology, 2006, Vol. 57, pp. 135-144);
the rejection of claim 37 under 35 U.S.C. 102(a)(1) as being anticipated by Dallavalle et al (Journal of Medicinal chemistry, 2000, vol. 43, pp. 3963-3969); and
the rejection of claims 37 and 39 under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al (Journal of Thoracic Oncology, 2012, Vol. 7, pp. 731-736)
is withdrawn in light of applicant’s amendment of claim 37.
The rejection of claims 37 and 39 under 35 U.S.C. 102(a)(1) as being anticipated by Cabri et al (WO96/37496) is withdrawn in light of applicant’s argument that the compound 101’ of Cabri is not part of claim 37.
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The rejection of claims 37 and 39 under 35 U.S.C. 102(a)(1) as being anticipated by Rougier et al (Journal of Clinical Oncology, 1997, Vol. 15, pp. 251-260) is maintained for reasons of record.
Rougier et al disclose the treatment of patients with advanced colorectal cancer comprising the administration of irinotecan, which meets the limitation of compound
PNG
media_image10.png
177
508
media_image10.png
Greyscale
in claim 37 and the method of claim 39.
Applicant argues that Rougier does not teach or suggest compounds as claimed in the currently amended claim 37. This has been considered but not found persuasive. Applicant is referred to page 21 of the instant claims, column 2, row 3 which shows the above structure.
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, 5, 6, 8, 11, 12, 13, 16, 18, 19, 22, 24, 30, 31, 38, 40, 44, 45, 50 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Woo et al (WO2024/005460, priority to KR-2022-78448, cited in the previous Action) as evidenced by US2025/0121072 (English Language version, cited in the previous action) and as evidenced by Lu et al (U.S. 2018/0055944, cited in the previous action) in view of Dickgiesser et al et al (Bioconjugate Chemistry, 2020, Vol. 31, pp. 1070-1076, cited in the previous action) and Dennler et al (Bioconjugate chemistry, 2014, Vol. 25, pp. 569-578).
Clam 1 has been amended to require that the first linker, L1, is connected to the side chain of a glutamine residue of the antibody or antigen-binding fragment thereof.
Woo et al teach antibody-drug conjugates comprising an antibody joined to a drug moiety by means of a linker/spacer linking the antibody to a triazole which is attached by a linker/spacer to the drug, “PL” (bottom of page 28 and top of page 29) wherein the drug, PL, is a camptothecin moiety:
PNG
media_image11.png
153
198
media_image11.png
Greyscale
(page 12), which meets the limitation of claim 1 for P-III, wherein R5 is H and R4 is -N(C1-C6alkyl) and (CH2)2. Woo et al teach an embodiment wherein the linker-drug may be bound to an antibody through the -C(=O)NH2 of glutamine (page 26, lines 20-33) which meets the limitations of claim 2. Woo et al teach that the antibody is Trastuzumab (paragraph [0139]) which meets the limitations of an anti-Her2 antibody in claim 6. Lu et al provide evidence that trastuzumab targets breast, lung and ovarian and prostate tumors (Table 2), thus the trastuzumab antibody of Woo et al meets the limitations of claim 8. Woo et al teach linker-drugs of “DAR4 type” in Table C, which meet the limitations of claims 30 and 31 for a DAR of about 0.5-about 12 and a DAR of 2, 4 or 8, as well as the limitations of claim 24 wherein n is 2 or 4. Woo et al teach pharmaceutical compositions of the inventive conjugates in a pharmaceutically acceptable carrier or excipient (paragraph [0212]) which meets the limitations of claim 38. Woo et all teach that the composition can be used for the treatment of cancers or tumors (paragraph [0219]) which meets the limitations of claim 39, as well as claims 44 and 45 because trastuzumab will target Her2 expressed o cancer cells and after receptor internalization, the conjugate will be taken up in the lysosomes for release of the camptothecin into the cell.
PNG
media_image12.png
211
343
media_image12.png
Greyscale
PNG
media_image13.png
282
384
media_image13.png
Greyscale
Woo et al disclose the linker-drug:
PNG
media_image14.png
138
364
media_image14.png
Greyscale
in Table B as of the DAR2 type (heading page 218 and structure page 222), which also meets the limitations of claims 30 and 31. the structure meets the limitations of having a first linker, L1, and a second linker, L2 joined together at the triazole, wherein L1 comprises C1-C6 alkyl in claim 12 and
PNG
media_image15.png
20
130
media_image15.png
Greyscale
and
PNG
media_image16.png
25
163
media_image16.png
Greyscale
in claim 13; wherein B comprises;
PNG
media_image17.png
62
67
media_image17.png
Greyscale
in claim 16, and SP2 is
PNG
media_image18.png
121
99
media_image18.png
Greyscale
which meets the limitations of claim 18, wherein SP1 and AA are absent, thus meeting that limitation in claim 19. Alternatively, with regard to claim 18, SP1 can be
PNG
media_image18.png
121
99
media_image18.png
Greyscale
and AA and SP2 can be considered as “absent”; which thus meets the limitations of claim 22 wherein SP2 is absent.
Claim 5 specifies, in part, that the glutamine residue in claim 2 is naturally present in the antibody. Claim 11 specifies, in part, that the glutamine residue of claim 2 is Q395.
Claim 50 is drawn to a method of making a compound of formula A wherein formula (A) has the same requirements as the compound of claim 1 except L1 is covalently bound to the side chain of a glutamine residue of the antibody, formed from contacting the antibody with L1-B in the presence of a transglutaminase, wherein B’ is N3 and B’’ is
PNG
media_image19.png
20
49
media_image19.png
Greyscale
.
Woo et al teach preparation of Linker P-1 having an azido group (page 43) and the preparation of linker P-2 having a
PNG
media_image19.png
20
49
media_image19.png
Greyscale
(page 44 (example 2).
Woo et al teach that the antibody may be bound to the linker through the -c(=O)NH2 of glutamine (paragraph [0135]), which meets the limitations of claim 2. Woo et al do not specifically teach that the glutamines are naturally present in the antibody or are Q295.
Dickgiesser et al teach the site-specific conjugation of native antibodies using engineered microbial transglutaminases (title).
Dickgiesser et al teach that the resulting ADCs have excellent stability in vitro as well as in vivo (abstract).
Dennler et al teach enzymatic and chemoenzymatic approaches for the formation of conjugates at antibody glutamine residues (page 574, figure 3). It is noted that structure 10 in Figure 3(A) would provide for L1 of instant claim 12 and claim 13:
PNG
media_image20.png
17
131
media_image20.png
Greyscale
. Dennler et al also teach that chemo-enzmatic approach utilizing a thiol group which was positions on an antibody glutamate by the transglutmnase, wherein the resulting protected thiol was deprotected and reacted with a linker payload (page 574, Figure 3(B), thiol-maleimide). Dennler et al teach that microbial transglutaminases specifically recognize Gln295 within the antibody heavy chain (abstract), which meets the limitations of claim 11
It would have been prima facie obvious at the time prior to the effective filing date to attach the L1-B’, wherein the B’ was either N3 or
PNG
media_image19.png
20
49
media_image19.png
Greyscale
, to the Q295 residue of the native antibody, BA by means of the engineered microbial transamidase, and then to carry out a 1, 3 cyclo addition with B’’-L2 having either
PNG
media_image19.png
20
49
media_image19.png
Greyscale
or N3 as B’’ to complement B’ and provide for the formation of the triazole, thus meeting the limitations f claim 50 and claim 51 as pertaining to “the compound of formula (A)”
One of skill in the art would have been motivated to do so because Woo et al teach the conjugation of L1 and L2 though a linker ending in
PNG
media_image19.png
20
49
media_image19.png
Greyscale
with a linker ending in N3 to form a triazole and couple both of the linkers. One of skill in the art would have been motivated to attach the L1 linker to the antibody at Q295 using the microbial transamidase because Dickgiesser et al teach that ADC conjugates attached to the antibody through Q295 glutamine exhibit excellent stability in vitro as well as in vivo.
Further, it would have been prima facie obvious in light of the teachings of Dennler et al, that the maleimide linker-payloads of Woo et al could be attached to an antibody having a glutamine modified to carry a protected thiol, as in Figure 3B of Dennler et al.
Applicant argues that the linker payloads of Woo contain a maleimide moiety indicating that they will be attached to the antibody through a Cys moiety, and that Woo et al teach that the trastuzumab payloads were specifically attached to a thiol group of the antibody.
This has been considered but not found persuasive. In response to applicant's argument that some exemplified structure of Woo comprise maleimide for the antibody conjugation, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Clearly, Woo et al teach as an alternative, the transglutaminase method of linking the linker payload to the antibody. One of skill in the art would understand that the resulting linker payloads would therefore be designed to have an alkyne, and the antibody would be modified through the enzymatic reaction of a transglutaminase to attach a primary amine carrying an azide group to Gln295 of the antibody. In the alternative, the maleimide linker-payloads of Woo et al could be attached to an antibody having a glutamine modified to carry a protected thiol, as in Figure 3B of Dennler et al.
Claims 1, 5, 6, 8, 11, 12, 13, 16, 19, 22, 24, 28, 30, 31, 38, 44, 45, 50 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Woo et al as evidenced by Lu et al in view of Dickgiesser et al and Dennler et al as applied to claims 1, 5, 6, 8, 11, 12, 13, 16, 19, 22, 24, 30, 31, 38, 44, 45, 50 and 51 above, and further in view of Gil et al (Synthesis, 2007, No. 11, pp. 1589-1620, cited in the previous Action).
Claim 28 requires a compound having the formula Alkyne-L2-P. Woo et al teach
PNG
media_image21.png
143
206
media_image21.png
Greyscale
which meets the limitation of PIII wherein R4 is -N(-C1-C6 alkyl) , and R5 is hydrogen. The A-73 compound of Woo et al has an azido group rather than an alkyne group.
Gil et al teach the Huisgen 1,3-dipolar cycloaddition for formation of a triazole from an azido group and an alkyne (page 1594, section 4).
It would have been prima facie obvious at the time prior to the effective filing date to swap the azido group on the end of the L2-P for
PNG
media_image22.png
45
60
media_image22.png
Greyscale
wherein R1 was L2-P. One of skill in the art would have been motivated to do so because the formation of the tetrazole resulted from the interaction of the pi bonds of the alkyne and the azido group which would be expected to produce the same product if the two moieties were attached to either L1 and L2. Thus, switching the azido group for
PNG
media_image22.png
45
60
media_image22.png
Greyscale
represents an art recognized equivalent for the precursors of the cycloaddition and results in the compound of claim 28.
Claims 20, 23, 27, and 29 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
All other rejections and/or objections as set forth in the prior Office action are withdrawn.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection 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 KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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, Julie Wu can be reached at 571-272-5205. 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.
KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
Prosecution Insights