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 .
Response to Election/Restriction filed on August 4,2026 is acknowledged.
Claims 1, 3-5, 15-26, 28-32, 34, 36-37 and 46-48 are pending in this application.
No foreign priority
Restriction
Applicant's election with traverse of Group 1 (claims 1, 3-5, 15-26, 28-32, 34 and 36-37) and election with traverse of the species for the FULLY DEFINED compound of formula I:
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in the reply filed on August 4, 2026 is acknowledged. The traversal is on the ground(s) that the Examiner has not explained how the specifically claimed compound of formula Ama-R1 fails to make a contribution over the cited reference, nor has the Examiner identified any teaching in Nixon et al. of the particular structural features recited in the claims. This is not found persuasive because instant claims and elected invention is drawn to a compound of formula I. Nixon et al (US 2017/0360954) teach formula (I)
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wherein the formula (I) encompasses instant formula I and the elected species
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. Nixon et al teach the same compound of formula I. Therefore, the lack of unity of invention has been established. Furthermore, in regard to the election of species and the species lacking unity, the species for example of a linker moiety lack unity of species since the linkers do not share a common core structure/sequence due to the different type of linkers (i.e., stable linker vs cleavable linker vs self-immolating moiety). Therefore, the lack of unity of species has been established. Applicant did not elect a species of a linker. The Examiner has elected to search a cleavable linker and the species was found in the art previously cited.
The requirement is still deemed proper and is therefore made FINAL. Claims 46-48 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected invention, there being no allowable generic or linking claim. Claims 16, 18 and 20 are withdrawn from consideration as being drawn to nonelected species found in the art. Claims 1, 3-5, 15, 17, 19, 21-26, 28-32, 34 and 36-37 are being examined on the merits in this office action.
Non-compliant amendment
The claim amendment filed on December 19, 2023 is non-compliant. The claim filed on June 6. 2023 had the following for claims 1 and 2:
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. In the claim amendment filed on December 19, 2023, claim 2 had been incorporated into claim 1 and claim 2 has been cancelled as follows:
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. Claim 1 amendment is non-compliant since the figure I (the structure) is not underlined. Additionally, the structure of formula I of claim filed on June 6, 2023 is
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and structure of formula I of claim filed on December 19, 2023 is
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. Thus, in the claim amendment filed on December 19, 2023, the structure of formula I is attached to a line, while the structure of formula I of claim filed on June 6, 2023 has a free methyl. Therefore, the structure of formula I in the claim amendment is different than the structure of formula I in the claim 2 filed on 6/6/2023. Therefore, the amendment filed on December 19, 2023 is non-compliant. Applicant is required to correct these errors in response to this office action.
Objections
6. The abstract is objected to for the following minor informality:
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words. It is important that the abstract not exceed 150 words in length since the space provided for the abstract on the computer tape used by the printer is limited. The form and legal phraseology often used in patent claims, such as "means" and "said," should be avoided. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, "The disclosure concerns," "The disclosure defined by this invention," "The disclosure describes," etc.
In the instant case, the abstract recites, “This application relates to amatoxin analogs...” at line 1 of the abstract. Further, at line 6, the abstract recites, "The application also relates to uses of such..." Applicant should correct these informalities. See MPEP 608.01(b). For example, the abstract at line 1 may be amended to recite, “Amatoxin analogs…are described.”
7. The drawings are objected to because some of the figures are missing the X and/or Y axis labels (see for example, FIGS. 1-8). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
8. Claim 1 is objected to for the following:
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. Claim 1 recites that R1 is not OH at line 3 and line 7 of the claim. Therefore, it appears that R1 is redundant. Applicant is required to correct this error.
Rejections
U.S.C. 112(b)
9. 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.
10. Claims 1, 3-5, 15, 17, 19, 21-26, 28-32, 34 and 36-37 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.
11. Claim 1 recites:
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. It is unclear if the R1 recited at lines 1-3 in the preamble of the claim is the same as the R1 recited at line 7 (after the structure of Formula I). Because claims 3-5, 15, 17, 19, 21-26, 28-32, 34 and 36-37 depend from indefinite claim 1 without clarifying the point of confusion, these claims are also rejected under 35 U.S.C. 112(b). For the purpose of the examination, the Examiner has interpreted that R1 is the same throughout claim 1.
12. Claims 15, 17, 19, 21-26, 28-32, 34 and 36-37 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 15 recites, “A compound-linker construct, comprising: the compound of claim 1 coupled to a linker, wherein the linker comprises a reactive group R10 for conjugating the compound-linker construct to a target-binding moiety.” The metes and bounds of the claim are unclear. Claim 15 depends from claim 1. Claim 1 recites the following:
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. It is unclear where the linker is attached to the compound of formula I. A clear definition of the structure of the compound-linker structure is not defined. Because claims 17, 19, 21-26, 28-32, 34 and 36-37 depend from indefinite claim 15 without clarifying the point of confusion, these claims are also rejected under 35 U.S.C. 112(b).
13. Claim 24 recites, “The compound-linker construct of claim 22, wherein Ama comprises a…moiety and the linker is coupled to the compound via a cyclic acetal obtained from reaction of the hydroxyl groups of the…” Claim 24 recites both a product and a method. Inventions. A claim cannot have more than one invention. Therefore, claim 24 has been interpreted as a product claim.
14. Claims 25 and 28, “The compound-linker construct of claim 24, wherein R1 is -CN” (claim 25) and “The compound-linker construct of claim 15, wherein R1 is -NH2” (claim 28). It is unclear what R1 Applicant is referring to. The metes and bounds of the claims are unclear. Applicant is required to clearly define what R1 is referring to.
15. Claim 30 recites the limitation "wherein n is 4" in line 2 of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 30 depends from claim 15. Claim 15 depends from claim 1. Claim 1 recites
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. Claim 1 does not recite a variable “n” in the claim. Therefore, there is lack of antecedent basis.
U.S.C. 102
16. 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.
17. 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.
18. Claim(s) 1, 3-4, 15, 17 and 19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nixon et al (US 2017/0360954, cited in the previous office action).
19. Nixon et al teach a compound of formula that encompasses instant formula I
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(see paragraphs [0035]-[0050], [0142]-[0171], for example). This is the same as instant formula I wherein R9 of Nixon is H, ORC or ORD, X of Nixon is -S-, -S(O)- or -SO2-, and R2 of Nixon is H, OH, ORC or ORD. This meets the limitation of instant claims 1 and 3-4. Nixon et al further teach that conjugates may include a linker between the two molecules bond to one another. Examples of linkers that can be used…include peptide-containing linkers…a linker may be cleaved, for example, by enzymatic hydrolysis, photolysis, hydrolysis under acidic conditions, hydrolysis under basic conditions, oxidation, disulfide reduction…(see paragraph [0283] for example), meeting the limitation of instant claims 15, 17 and 19. Because Nixon et al teach ALL of the active components of instant claims, Nixon et al anticipates instant claims 1, 3-4, 15, 17 and 19.
20. Claim(s) 1, 3-4, 15, 17, 19 and 21-22 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhu et al (EP 3735987, filed with IDS).
21. Zhu et al teach a toxin conjugate of structural formula (I) or a pharmaceutically acceptable salt thereof:
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(see paragraphs [0006]-[0007]). Since the R1 of the compound of structural formula (I) of Zhu et al is not OH, and the conjugate comprises a cleavable or non-cleavable linker comprising, for example,
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, this meets the limitation of instant claims 1, 3-4, 15, 17, 19 and 21-22.
U.S.C. 103
22. 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.
23. 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.
24. 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.
25. 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.
26. Claim(s) 1, 3-4, 15, 17, 19 and 21-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lutz et al (Angew. Chem. Int. Ed., 6/7/2020, 59: 11390-11393, filed with IDS) in view of Nixon et al (US 2017/0360954, cited in the previous office action) and Zhu et al (EP 3735987, filed with IDS).
27. Lutz et al teach alpha and beta amanitin
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(amatoxin analogs) (see Scheme 1). Lutz et al teach a method for the total synthesis of an amatoxin of instant claim 1.
The difference between Lutz et al and instant claims is that Lutz et al does not teach R1 is not OH (as can be seen from the structure above, R1 is OH in Lutz et al).
28. However, Nixon et al teach
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(see paragraphs [0035]-[0050], [0142]-[0171], for example).
29. Additionally, Zhu et al teach
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(see paragraphs [0006]-[0007], for example). Zhu et al teach that the conjugates are stable in blood plasma and decomposes into a drug as an active ingredient in a specific biological environment, thereby maximizing the activity on target cells and minimizing toxic side effects on non-target cells (see abstract, for example).
30. Therefore, it would have been obvious to one of ordinary skill in the art to combine the teachings of Lutz et al, Nixon et al and Zhu et al to arrive at the amatoxin analogs of instant formula I, since all of the references teach amatoxin analogs and method of making the analogs. One of ordinary skill in the art would be motivated to combine with a reasonable expectation of success, since both Nixon et al and Zhu et al teach that R1 is not OH, and Zhu et al teach that conjugates can be made with a cleavable and non-cleavable linker. Zhu et al further teach that the conjugates are stable in blood plasma and decomposes into a drug as an active ingredient in a specific biological environment, thereby maximizing the activity on target cells and minimizing toxic side effects on non-target cells. Therefore, one of ordinary skill in the art would make the amatoxin analogs wherein R1 is not OH and conjugates comprising different linkers, including
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, with a reasonable expectation that these analogs will be more stable.
DOUBLE PATENTING
31. 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.
32. Claims 1, 3-5, 15, 17, 19, 21-26, 28-32, 34 and 36-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 12,544,419 in view of Nixon et al (US 2017/0360954, cited in the previous office action) and Zhu et al (EP 3735987, filed with IDS).
33. Instant claims are drawn to:
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34. US Patent claims are drawn to:
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.
The difference between the US Patent claims and instant claims is that in the instant claims R1 is not OH.
35. However, Nixon et al teach a compound of formula that encompasses instant formula I
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(see paragraphs [0035]-[0050], [0142]-[0171], for example). This is the same as instant formula I wherein R9 of Nixon is H, ORC or ORD, X of Nixon is -S-, -S(O)- or -SO2-, and R2 of Nixon is H, OH, ORC or ORD. This meets the limitation of instant claims 1 and 3-4. Nixon et al further teach that conjugates may include a linker between the two molecules bond to one another. Examples of linkers that can be used…include peptide-containing linkers…a linker may be cleaved, for example, by enzymatic hydrolysis, photolysis, hydrolysis under acidic conditions, hydrolysis under basic conditions, oxidation, disulfide reduction…(see paragraph [0283] for example).
36. Further, Zhu et al teach a toxin conjugate of structural formula (I) or a pharmaceutically acceptable salt thereof:
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(see paragraphs [0006]-[0007]). Since the R1 of the compound of structural formula (I) of Zhu et al is not OH, and the conjugate comprises a cleavable or non-cleavable linker comprising, for example,
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. Zhu et al teach that the conjugates are stable in blood plasma and decomposes into a drug as an active ingredient in a specific biological environment, thereby maximizing the activity on target cells and minimizing toxic side effects on non-target cells (see abstract, for example).
37. Therefore, since both Nixon et al and Zhu et al teach amatoxin analogs wherein R1 is not OH, and conjugates thereof, it would have been obvious to one of ordinary skill in the art to make analogs wherein R1 is not OH. One of ordinary skill in the art would be motivated to make the analogs wherein R1 is not OH, since both Nixon et al and Zhu et al teach that it is successful and altering the R1 will not alter the activity of the amatoxin analogs.
CONCLUSION
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JULIE HA whose telephone number is (571)272-5982. The examiner can normally be reached Monday-Thursday 5:00 am- 6:30 pm EST.
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, LIANKO GARYU can be reached at 571-270-7367. 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.
/JULIE HA/Primary Examiner, Art Unit 1654
9/2/2026
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