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 .
Status of the Claims
Claims 1 – 27 and newly added claims 28 – 30 are pending.
Claims 7 – 12 and 17 – 21 are rejected.
Claims 28 – 30 are objected.
Claims 1 – 6, 13 – 16 and 22 – 27 are withdrawn.
Response to Applicant’s Remarks
Applicant’s remarks and amendments filed on March 17, 2026 and May 21, 2026.
The objections to claims 7, 9 – 10, 16 – 17 are withdrawn in view of amendments to recite proper grammar and Markush group language in each claim.
The rejection under 35 U.S.C. §112(b) of claims 11 – 12 is partially withdrawn in view of amendments to delete the narrower limitations from the claims. However, it is noted that claim 11 still recites a narrower limitation comprising the phrase “preferably”. See, claim 11, page 7, line 2 of the claim. Thus, the rejection is maintained and amended to address the limitation.
Regarding the rejection under 35 U.S.C. §103 of claims 7 – 12 and 17 – 21 (correctly amended, previously labeled claims 16 – 20) as being unpatentable over Xu et al. CA3114137 A1 (pub. April 2, 2020) in view of Timmins et al., Expert Opin Ther Pat. Author manuscript (2015), pp. 1-19, Applicant’s remarks have been considered and discussed below:
On page 3, 2nd – 3rd paragraphs, Applicant summarizes the scope and contents of the prior art. On page 3, 4th – 5th paragraphs, Applicant states that the claimed invention is patentably distinct from Xu et al. because compound ADC-1 in Xu does not teach the substitution of deuterium for hydrogen at the Ra position, rather than the fluorine-bearing CF3 group of Xu’s ADC-1. However, it is noted that Applicant has addressed an incorrect scope of difference between the prior art and the instant claims. The scope of issue is the moiety -CRaRb (carbon atom connecting the carbonyl (-C(=O)) moiety, trifluoromethyl (-CF3) moiety and ester bond (-O-) in the variable X of Formula -L-X-D2. In the moiety -CRaRb, one of Ra or Rb is hydrogen, and the other is -CF3. The basis of issue is the hydrogen atom (not the trifluoromethyl (-CF3) moiety) bonded to one of Ra or Rb being replaced by a deuterium atom. Emphasis added.
On page 3, 6th paragraph – page 5, 1st paragraph, Applicant discusses four reasons that prima facie case of obviousness has not been established. First, Applicant notes that Xu only generically and broadly discloses deuteration to Formula (I) and does not specifically identify the X connector unit, or the carbon alpha to the carbonyl and oxygen in the connector unit, as a target for metabolic stabilization. General disclosure of the possibility of deuteration does not establish a reasonable expectation of success. Second, Applicant notes that Timmins explicitly cautions that deuterium substitution does not universally improve the pharmacokinetics and that successful deuterated drug development requires ‘identification of a metabolic soft-spot’ and careful study of the DKIE at the specific site of metabolism. Third, Applicant refers that Examples 21-24 in the specification demonstrates the precise purpose and benefit of deuterium incorporation at the X connector unit. Applicant further points to the substitution of the CF3 group in Xu’s ADC-1 and states that replacing CF3 with deuterium is not an equivalent substitutions due to the different chemical functions. Fourth, Applicant further discusses the fluorine-bearing electron-withdrawing group, -CF3, as taught in Xu’s ADC-1, which is fundamentally different from the scope of the instant claims. Thus, Applicant concludes that the combination of Xu and Timmins does not establish prima facie case of obviousness and the rejection relies on hindsight reconstruction.
However, it is noted that Xu does not only generically or broadly discloses deuteration to Formula (I). Xu specifically teaches (see, e.g., pp. 53, lines 7-13):
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While Xu does not specifically identify the X connector unit, Xu further teaches a method of preparing the compound of formula (D1) (see, e.g., pp. 56, lines 10-15):
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.
Xu provides guidance that α-carbon (-C(R1)(R2)) connected to the carbonyl and oxygen in the connector unit is critical location in the process for preparing compounds of formula (D1). A person having ordinary skill in the art would consider the α-carbon as a good starting point and would be motivated to deuterate the drug-linker compound of Formula -L-X-D2. The test for obviousness is not whether the features of a secondary reference (Timmins) 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). Timmins also teaches “[s]ince there is always a desire to modify a compounds pharmacological effects (exemplified by deuteration improvements in half-life) without significant structure modification, or the need to improve pharmacokinetic studies, yet there being only a limited number of strategies to achieve this, obviousness of these solutions is found”. See, Timmins et al., page 4, 1st-2nd paragraphs. Thus, the PHOSITA would have been motivated to specifically select and deuterate the α-carbon -CRaRb (in Formula -L-X-D2), wherein one of Ra or Rb is hydrogen, as the starting position in order to perform routine experimentation to make and test the deuterated compound of ADC-1 because said compound is identified in Xu as a lead compound. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Thus, Applicant’s remarks are not persuasive and the rejection is maintained.
Regarding the provisional nonstatutory double patenting rejection of claims 7 – 12 and 17 – 21 (correctly amended, previously labeled claims 16 – 20) as being unpatentable over claims 9 – 15 and 18 – 21 of copending Application No. 18/030,754 in view of Timmins et al., Expert Opin Ther Pat. Author manuscript (2015), pp. 1-19, Applicant requests the rejection to be held in abeyance pending allowance of the instant claims. Additionally, Applicant refer to the remarks addressed in the 103 rejection to state that the claims are patentably distinct from the claims of 18/030,754. Since the remarks in the 103 rejection are not persuasive, the provisional nonstatutory double patenting rejection is also maintained.
Claim Objections
Claims 28 – 30 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.
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.
Claim 11 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, 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,
Claim 11 recites the broad recitation “The drug-linker compound according to claim 9 or a pharmaceutically acceptable salt or solvent thereof”. See, lines 1-2 of the claim. The broad limitation refers to the definition of L3 as claimed in claim 9. Claim 11 also recites the limitation “L3 is preferably a peptide comprising one, two, or more amine acids selected from phenylalanine and glycine, which is the narrower statement of the range/limitation.
The claim is 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. In order to overcome the rejection, Applicant may amend as follows:
Claim 11, lines 2 – 3 of the claim: “… L3 is
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.
Claims 7 – 12 and 17 – 21 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. CA3114137 A1 (pub. April 2, 2020) in view of Timmins et al., Expert Opin Ther Pat. Author manuscript (2015), pp. 1-19.
Determining the scope and contents of the prior art
Xu et al. teach an antibody-drug conjugate (ADC-1) of Example 21. See, e.g., page 113, lines 1-2. The antibody-drug conjugate (ADC-1) of Example 21 is presented below:
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,
wherein: n is 5.09. See, e.g., page 113, line 16.
Compared to instant claims, the antibody-drug conjugate (ADC-1) of Example 21 teach the drug-linker compound of Formula -L-X-D2 as presented below:
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, wherein:
R2, R2’, R3, R3’, R4, R4’, R5, R5’, R8, R9 and R10 are hydrogen,
R1 and R7 are C1 alkyl,
X is -C(O)-CRaRb-(CRcRd)n-O-,
n is 0,
One of Ra or Rb is hydrogen, and the other is -CF3,
L is
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,
the linker unit L is -L1-L2-L3-L4-:
L1 is –(Succinimido-3-yl)-Y-C(O),
Y is C5 alkyl,
L2 is a chemical bond or -NR6(CH2CH2O)pCH2C(O)-, wherein p is 0 and R6 is hydrogen,
L3 is a peptide residue having 3-4 amino acids, and
L4 is -NR7(CR8R9)q-, wherein q is 1, and R7, R8 and R9 are hydrogen.
Ascertaining the differences between the prior art and the claims at issue
The difference between the antibody-drug conjugate (ADC-1) of Example 21 and the claims is that hydrogen atom is bonded to one of Ra or Rb in variable X (in compound ADC-1)
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instead of deuterium as instantly claimed
Rationale for a prima facie case of obviousness
According to MPEP §2141(III), one of the rationales in the KSR decision states “(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention”. KSR, 550 U.S. at 418, 82 USPQ2d at 1396. While Xu does not explicitly disclose the deuterated form of the antibody-drug conjugate (ADC-1) of Example 21, Xu teaches that the compounds of generic formula (I) can be present in various deuterated forms. Xu states “[e]ach of the available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom… [t]hose skilled in the art can synthesize a compound of formula (I) in a deuterated form with reference to the relevant literatures… [t]he compound of formula (I) in deuterated form can be prepared by employing commercially available deuterated raw materials, or they can be synthesized by conventional techniques with deuterated reagents…”. See, e.g., page 53, lines 7-13. It would have been obvious to a person having ordinary skill in the art to deuterate the drug-linker compound of Formula -L-X-D2 given there is always a need to enhance the pharmaceutical properties of a compound (e.g., increased in vivo half-life) without significantly altering its basic chemical structure, or there is always a need to reduce the time, cost, risk, and statistical imprecision of pharmacokinetic studies (e.g., measure bioavailability or identify metabolites), and there is only a limited number of ways that this can be done, it would have been obvious to a PHOSITA to pursue a potential solution that has a reasonable expectation of success. See, e.g., Timmins et al., page 4, 1st-2nd paragraphs; KSR International Co. v. Teleflex Inc., 1385, 1397; Pfizer, Inc. v. Apotex, Inc., 82 USPQ2d 1321; Alza Corp. v. Mylan Laboratories, Inc., 80 USPQ2d 1001; In re Kubin, 90 USPQ2d 1417; In re O’Farrell, 7 USPQ2d 1673, 1681; In re Eli Lilly & Co., 14 USPQ2d 1741; In re Ball Corp., 18 USPQ2d 1491.
Double Patenting
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.
Claims 7 – 12 and 17 – 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9 – 15 and 18 – 21 of copending Application No. 18/030,754 (U.S. Publication 2025/0276078 A1) in view of Timmins et al., Expert Opin Ther Pat. Author manuscript (2015), pp. 1-19. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Determining the scope and contents of the copending Application
Claim 9 in US ‘754 claims a linker-drug conjugate comprising the camptothecin derivative L-X-D:
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Claim 21 in US ‘754 specifically claims the conjugate:
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wherein: Ab is a ligand unit, and n is selected from integers or decimals within 1-20.
With respect to instant claims, the claims in US ‘754 teach the antibody-drug conjugate, wherein hydrogen atoms are bonded to the carbon atom in variable X
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instead of containing at least one deuterium.
The specification of US ‘754 defines “[t]he invention also includes various forms of deuteration… [e]ach available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom… [a] person skilled in the art of this field can synthesize deuterated compounds by referring to relevant literature… [i]n the preparation of deuterium compounds, commercially available deuterium initiation materials may be used, or they may be synthesized using conventional techniques using deuterium reagents”. See, e.g., page 57, lines 16 – 21. It would have been obvious to a person having ordinary skill in the art to deuterate the drug-linker compound of Formula -L-X-D2 given there is always a need to enhance the pharmaceutical properties of a compound (e.g., increased in vivo half-life) without significantly altering its basic chemical structure, or there is always a need to reduce the time, cost, risk, and statistical imprecision of pharmacokinetic studies (e.g., measure bioavailability or identify metabolites), and there is only a limited number of ways that this can be done, it would have been obvious to a PHOSITA to pursue a potential solution that has a reasonable expectation of success. See, e.g., Timmins et al., page 4, 1st-2nd paragraphs; KSR International Co. v. Teleflex Inc., 1385, 1397; Pfizer, Inc. v. Apotex, Inc., 82 USPQ2d 1321; Alza Corp. v. Mylan Laboratories, Inc., 80 USPQ2d 1001; In re Kubin, 90 USPQ2d 1417; In re O’Farrell, 7 USPQ2d 1673, 1681; In re Eli Lilly & Co., 14 USPQ2d 1741; In re Ball Corp., 18 USPQ2d 1491.
The claims in US ‘754 render the instant claims unpatentable for obvious-type double patenting.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
THIS ACTION IS MADE FINAL. 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 Sagar Patel whose telephone number is (571)272-1317. The examiner can normally be reached Monday - Friday: 9am to 5pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L. Clark can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Sagar Patel/Examiner, Art Unit 1626
/KAMAL A SAEED/Primary Examiner, Art Unit 1626
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