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 . 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.
Election/Restrictions
Applicants elected group I (conjugates) and the compound of claim 183 without traverse in the reply filed on 25 March, 2025. In the response of 10 July, 2025, applicants amended their claims so they no longer read on applicant’s elected species.
Claims Status
Claims 144, 160, 163, 171, 172, 177-180, 184, and 187 are pending.
Claims 144, 160, and 163 have been amended.
Claims 172, 177-180, and 184 have been withdrawn due to an election/restriction requirement.
Withdrawn Rejections
The rejection of claims 144-154, 158-165, 168, 169, 171, and 187 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite due to the vague and ambiguous definition of the various portions of the linker and how they can be partitioned among an embodiment is hereby withdrawn due to amendment.
The rejection of claims 144-154, 158-165, 168, 169, 171, and 187 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite due to uncertainty as to where attachments are made to the camptothecin is hereby withdrawn due to amendment.
The rejection of claim 151 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite due to lack of antecedent support is hereby withdrawn due to amendment.
The rejection of claims 144-154, 158-165, 168, 169, 171, 183, and 187 under 35 U.S.C. 103 as being unpatentable over Yao et al (Int. J. Mol. Sci. (2016) 17(194)) in view of Beau-Larvor et al (US 20150037340, referred to as Beau-Larvor1 in this rejection), Beau-Larvor et al (US 20160106861, referred to as Beau-Larvor2 in this rejection), and Wadkins et al (Canc. Res. (2004) 64 p6679-6683) is hereby withdrawn due to amendment.
The provisional rejection of claims 144-151, 158-161, 168, 171, and 187 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 63, and 76 of copending Application No. 18/185,341 (US 20230381321) in view of Wadkins et al (Canc. Res. (2004) 64 p6679-6683) is hereby withdrawn due to amendment.
The provisional rejection of claims 144-154, 158-165, 168, 169, 171, and 187 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 7, 21, 29, and 72 of copending Application No. 17/766,208 (US 20240277860) is hereby withdrawn due to amendment.
The provisional rejection of claims 144-154, 158-165, 168, 169, 171, and 187 on the ground of nonstatutory double patenting as being unpatentable over claims 87, 105, 112, 115, and 118 of copending Application No. 17/061,998 (US 20210101982) is hereby withdrawn due to amendment.
The provisional rejection of claims 144-154, 158-165, 168, 169, 171, and 187 on the ground of nonstatutory double patenting as being unpatentable over claims 2, 13, and 14 of copending Application No. 18/039,473 (US 20240076394) is hereby withdrawn due to amendment.
The provisional rejection of claims 144-154, 158-165, 168, 169, 171, and 187 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 32, 36, 45, and 46 of copending Application No. 17/924,964 (US 20230190949) is hereby withdrawn due to amendment.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 112(a)
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 144, 160, 163, 171, and 187 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.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure (MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The issue is if a person of skill in the art could determine what species are a ligand unit.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: A ligand unit is defined as a targeting agent that specifically binds to a target moiety (paragraph 127). Preferred ligand units are antibodies (paragraph 139), but there is no limitation that it actually be a polypeptide, much less an antibody. A small number of specific antibodies are discussed (paragraph 152)
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure: Applicants are claiming an invention with a moiety that binds specifically to an unspecified target moiety. This requires that the material have the functional ability to specifically bind to an unspecified target. However, applicants have not described what structural features are required to meet this functional limitation. A person of skill in the art would not know what physical/sequence/chemical features are required to specifically bind. In essence, applicants have defined an important part of their invention by function. That is not sufficient to meet the written description requirement.
As of applicant’s priority date, it was not possible to determine what a given compound would bind to without actually testing for binding, absent such interactions as base pair coupling of nucleotides. Lowe (Blog “In the pipeline, entry of 7 Sept, 2022, cited by applicants) discusses an experiment to determine if current computational methods were up to the task. 218 compounds that were found to have growth inhibition activity against E. coli were screened in silico against 296 essential proteins from the bacterium, using a number of different approaches (1st page, 3d paragraph). The number of strong binding interactions was essentially the same between these active compounds and a control set of inactive compounds (2nd page, 2nd paragraph). Of these 218 compounds and 296 proteins were 142 previously known compound/target interactions; the computer approach found only 3 of them (2nd page, 2nd paragraph). In other words, the number of false positive and false negative errors were high enough to totally swamp any signal found. While a given computer approach may give a good result for a given target/compound pair, it is impossible to tell a priori which ones they are (1st page, 2nd paragraph). As of well after applicant’s priority date, this reference demonstrates that there is no way to determine what compounds bind to what targets without actually physically contacting the two.
It should be noted that specifying an antibody that binds to a given target, without describing the sequence in the variable region of the antibody responsible for binding, is no longer sufficient to meet the written description requirement (MPEP 2163(II)(A)(3)(a)). In other words, specific antibodies, with known sequence, must be used to meet the written description requirement; a generic “anti-xxxx” antibody is not sufficient.
(d) representative number of samples: Applicants have described a small number of antibodies to a small number of targets. Given that the ligand unit is not limited to antibodies, and the target moiety is entirely undefined, this is not sufficient to meet the written description requirement.
response to applicant’s arguments
Applicants argue that they have amended around this rejection.
Applicant's arguments filed 10 July, 2025 have been fully considered but they are not persuasive.
The rejection is based on the Ligand Unit of claim 144; applicants have made no amendments to that portion of the claims.
New Rejections
Claim Rejections - 35 USC § 112(a)
The legal basis for rejections under this statute was given above, and will not be repeated here.
Claims 144, 160, 163, 171, and 187 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.
Applicants have required the group
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to be attached directly to the canptothecin. While applicants have support for this group (paragraph 243), the specification has this group attached to RF. And RF, while allowing for a great deal of variability, cannot be a bond. Thus, this amendment constitutes new matter.
Claim Rejections - 35 USC § 112(b)
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 144, 160, 163, 171, and 187 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.
Claim 144, and claims dependent on it, has a variable p, which is not defined. This makes the claims indefinite.
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.
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.
Claim(s) 144, 160, 163, 171, and 187 are rejected under 35 U.S.C. 103 as being unpatentable over Masuda et al (US 20150297748) in view of Wadkins et al (Canc. Res. (2004) 64 p6679-6683, cited by applicants).
Masuda et al discuss antibody drug conjugates (title). Among the compounds synthesized is:
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(example 58, paragraph 812). Note that there are a number of variants of this, varying the number of linker-drug moieties attached to the antibody or alternative syntheses (examples 58-76, paragraphs 812-937), and this particular linker-drug moiety is explicitly claimed by the authors (claim 46). In the language of applicants, Y=
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, RL=GGFG, a tetrapeptide, A=a bond, and Z=
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. While this particular example used exatecan, other camptothecin derivatives can be used (paragraph 266). Purification of the compounds uses size exclusion chromatography in PBS (paragraph 333), a pharmaceutically acceptable carrier.
The difference between this reference and the examined claims is that this reference uses a different camptothecin derivative.
Wadkins et al discuss hydrophilic camptothecin analogs (title). Various hydrophilic groups were attached to position RF (applicant’s terminology) to create analogs similar to CPT5 of applicants (fig 2, p6681, top of page). The 1-3 dioxolane deriveatives had better affinity than their corresponding non-dioxalone derivatives, and the more hydrophilic the adduct at position RF, the more active the camptothecin analog (abstract and table 1, p6680, top of page). This reference teaches camtothecin analogs of greater activity and that the RF position is tolerant to modification.
Therefore, it would be obvious to subtitute the camptothecin analogs of Wadkins et al, as those derivatives have much better activity than the native camptothecin. As Masuda et al explicitly state that other camptothecin analogs can be used, an artisan in this field would attempt this modification with a reasonable expectation of success.
Masuda et al describe an antibody-drug conjugate with camptothecin attached to the Y unit of applicants, attached to a tetrapeptide, attached to a hexanoic acid attached to a maleimide to an antibody. Wadkins et al renders obvious using the camptothecin analog of the competing claims, rendering obvious claims 144 and 160.
The tetrapeptide of the example of Masuda et al is Gly-Gly-Phe-Gly, rendering obvious claim 163.
Masuda et al uses an antibody, rendering obvious claim 171.
Masuda et al describes purifying their conjugates into PBS, rendering obvious claim 187.
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 FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
Examiner interviews are available via telephone 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, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658