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.
DETAILED ACTION
Claims 1-20 are pending in the instant application.
Priority
This application is a 371 of PCT/CN2021/097302, filed on 5/31/2021 which claims priority to the foreign application CN202010510363.5 filed on 6/8/2020.
Sequence Compliance
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures: 37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Claims 1, 9-10, and 14-15 include the amino acid sequence GGFG, but there is no corresponding SEQ ID NO in the claims, specification, or in the sequence listing.
Information Disclosure Statement
The information disclosure statement (IDS) dated 12/7/2022 complies with the provisions of 27 CFR 1.97, 1.98, and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits.
Objections to the Claims
Claim 8, line 3, “Hydrophilic” does not need to be capitalized. Furthermore the adjective of “hydrophilic structure” is redundant to describe polyethylene glycol, which is inherently a hydrophilic structure. Please delete “Hydrophilic structure”.
Claims 9, 18-19 refers to a single claim using the language “to any one of claim”. Please delete and replace with “of claim”.
Claims 10 and 17, refer to variables as “are as described in Formula II”. These variable definitions need to be repeated in these individual claims because they do not depend on a claim that describes them.
Claims 15, refer to variables as “are as defined in Formula II”. These variable definitions need to be repeated in these individual claims because they do not depend on a claim that describes them.
Claim 14 lacks and “or” between the last two structures.
Claim 18, line 3 requires a semi-colon to differentiate the lists and sub-lists. Please replace “solvate thereof, and a” with “solvate thereof; and a”.
Claim 20, line 1 uses the wrong tense. Please replace “comprising” with “comprises”.
Claim 20, line 6 contains three conjunctions. There should only be one conjunction between the last two list items.
Claim 20, line 6 contains a list item that is not a cancer. Please delete “hematoma drugs”.
Correction is required. See MPEP § 608.01(m).
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 1-20 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.
All claims
Claims 1, 5, 7, 9-10, 15, and 17 are drawn to "the position-1 carbon and position-4 chiral carbon each has the chirality of R or S configuration;” wherein it is unclear if applicant is indicating (i) simply that carbon 1 is a chiral center; or (ii) that the conjugate is non-racemic (i.e. only the S, or only the R isomer). One artisan may assume Applicant is merely highlighting the only two options of a binary situation; reiterating an inherent property of chiral carbons. Another artisan might conclude that applicant is ruling out mixtures of conjugates comprising both the R and S isomers at this carbon (i.e. the mixture contains only the R isomer). As a result of these multiple interpretations, this claim is rendered indefinite. Dependent claims 2-4, 6, 8, 11-14, 16, and 18-20 fail to cure these deficiencies, thus are also rendered indefinite. Presuming Applicant prefers interpretation (i), Examiner recommends deleting “the position-1 carbon and position-4 chiral carbon each has the chirality of R or S configuration;” from claims 1, 5, 7, 9-10, 15, and 17 to overcome this rejection.
Claim 4
Claim 4 is drawn to the group “Ac” being an amino acid residue such as alanine, wherein it is unclear how the amino acid is bonded. Amino acids can be both monovalent and divalent. Importantly, claim 4 is not dependent on claim 3, thus can have a structure other than that of claim 3. One artisan may presume it is limited to structures of -NH-Y-X as specified in claim 3, thus the example of alanine is limited to -NH-(CH2-Me)-COOH. Another artisan could interpret this as including both monovalent species (-C(O)-(CH2-Me)-NH2 and -NH-(CH2-Me)-COOH). While another artisan could interpret this as broadly as “comprises alanine” in any fashion, such as the amino acid sequence PPPAGYN. The interpretation of this claim is further complicated because claim 1 specifies that Ac is a “hydrophilic structural unit” wherein the claimed amino acid residues such as alanine, valine, leucine, and isoleucine are hydrophobic. Because of these multiple interpretations, this claim is rendered indefinite.
Claim 11
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 “an antibody, an antibody fragment, or a protein,” and the claim also recites:
“wherein the antibody is selected from murine antibodies, rabbit antibodies, phage display antibodies, yeast display antibodies, chimeric antibodies, humanized antibodies fully human antibodies, antibody fragments, bispecific antibodies, or multi-specific antibodies”
which is 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.
Claim 15-16
Claim 16 is drawn to a deprotection step that converts Formula IV into Formula II (depicted below), wherein there is no clear protecting group nor the depiction of a consequently deprotected group
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In claim 7, Formula II, the “Ac” group “is a hydrophilic structural unit”. In claim 15, Formula IV, “R2 is configured to form Ac”. Given this description, one of skill in the art would not know what the relationship or R2 and Ac are. In one interpretation they could be the same functional group. In another interpretation, R2 could just be the hydrate or HCl salt of Ac. Applicant has failed to provide a definition explaining what “configured to form” means. As a result, one of skill in the art would not be apprised of the metes and bounds of claims 15-16, thus rendering these claims indefinite.
Claim 19
Claim 19 is a product claim that appears to be reciting a method step of “for use in the preparation of a drug for the treatment of cancer” said product. MPEP § 2173.05(p)(II) recites:
“Product and Process in the Same Claim
“A single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. See In re Katz Interactive Call Processing Patent Litigation, 639 F.3d 1303, 1318, 97 USPQ2d 1737, 1748-49 (Fed. Cir. 2011). In Katz, a claim directed to “[a] system with an interface means for providing automated voice messages…to certain of said individual callers, wherein said certain of said individual callers digitally enter data” was determined to be indefinite because the italicized claim limitation is not directed to the system, but rather to actions of the individual callers, which creates confusion as to when direct infringement occurs. Katz, 639 F.3d at 1318, 97 USPQ2d at 1749 (citing IPXL Holdings v. Amazon.com, Inc., 430 F.3d 1377, 1384, 77 USPQ2d 1140, 1145 (Fed. Cir. 2005)”.
In the instant case, claim 19 is rendered indefinite because it is a composition claim that claims a particular use (e.g. use in drug preparation or use in treating), thus rendering this claim indefinite. Dependent claim 20 fails to cure these deficiencies, thus is also rendered indefinite.
Claim 19-20
Claim 20 is drawn to a method of “the use according to claim 19”, wherein claim 19 is a product claim and not a method. The method(s) of claim 19-20 lack any positive steps towards completing the claimed method. Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. For example, a claim which read: “[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon” was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986). See MPEP § 2173.05(q).
Claim Rejections – 35 USC § 102
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.
Claims 1-2, 5-8, 10-13, and 18-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Naito (US20170035906).
Claim 1,7, 10
Regarding claims 1, 7, and 10, Naito teaches the linker formula below (pg 43, para 00170, last structure),
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Wherein n3 is 1; Lp is an amino acid linker of GGFG (pg 45, para 1178); wherein “the —NH—(CH2)n1 -La-Lb-Lc-“ moiety can be —NH—CH2-O—CH2-C(=O)— (pg 45, para 1179); wherein the “—(NH-DX)” is the camptothecin shown below (pg 8, para 0096).
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In one exemplary species, Naito teaches the structure below wherein the 1 position carbon is chiral and of the S configuration (arrow) featuring a hydrophilic carboxylic acid group (pg 250, Example 118). The phenylalanine residue (F) is also chiral in the S configuration (shown below).
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Naito teaches the number of conjugated drugs per antibody is 1 to 10 (pg 24, para 0487).
In sum, Naito teaches the following structural limitations, wherein DX is Exatecan; Ab is trastuzumab; and m is 0. The atom numbering is that defined by instant claim 1.
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Claim 2
Regarding claim 2, Naito teaches succinimide (instant Formula a), shown above (pg 250, Example 118).
Claim 5-6
Regarding claims 5-6, Naito teaches the drug comprises the following structural features shown below, which satisfies the conditions wherein instant R1 is hydrogen; m is 0; and the hydroxyl occupies instant position 3 (pg 45, para 1179; pg 8, para 0096). This also satisfies the limitations of claim 6, structure d1.
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Claim 8
Regarding claim 8, Naito teaches the Ac unit is (S) glutamic acid, shown above (arrow) (pg 250, Example 118).
Claim 11-12
Regarding claims 11-12, Naito teaches the antibody is trastuzumab, which is a humanized anti-HER2 monoclonal antibody (pg 11, para 0136-0137).
Claim 13
Regarding claim 13, Naito teaches trastuzumab comprises the heavy chain of SEQ ID NO: 1 (instant SEQ ID NO: 2) and the light chain of SEQ ID NO: 2 (instant SEQ ID NO: 2).
Claim 18
Regarding claim 18, Naito teaches pharmaceutical composition comprising the conjugate and a pharmaceutically-acceptable carrier (pg 73-74, para 1424),
Claim 19-20
Regarding claim 19-20, Naito teaches the pharmaceutical composition can be administered as an anti-cancer therapeutic (pg 73, para 1416, 1419-1420), wherein the cancer is breast cancer (pg 73, para 1421).
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 1-14 and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Naito (US20170035906) as applied to claims 1-2, 5-8, 10-13, and 18-20 above, and further in view of Zhu (CA3095067A1) and Kierzek (Tetrahedron Letters (1981)).
claim 3-4
Regarding claims 3-4, Naito does not teach Ac comprises NH-Y-X.
Zhu teaches an ADC of Formula I that is effective in treating cancer (pg 1, para 1), shown below (pg 7).
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Zhu teaches M is a succinimide of the structure below (pg 9).
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Zhu teaches Ac comprises NH-(CH2)2-COOH, shown below (pg 9).
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This satisfies the limitation wherein Ac is the structure below.
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It would have been obvious to combine the teachings of Naito and Zhu because both are drawn to the generation of antibody drug conjugates featuring an antibody, a maleimide unit, an amino acid unit, and a drug unit in the same linear order. Naito teaches all of the structural limitations of the claims excluding variations of the Ac unit comprising NH-Y-X; and Zhu supplies the necessary information that such Ac units are compatible with ADC’s that are designed for treating cancer. One of skill in the art would have had a reasonable expectation of success because the additional structural unit of Ac supplied by Zhu has been demonstrated as an effective moiety in an anti-cancer ADC.
claim 9
Regarding claim 9, Naito does not teach Ac comprises NH-Y-X.
Zhu teaches Ac is 2-(NH)pentanedioic acid, wherein the position 1 carbon is in the S configuration, circled below (pg 35, compound 20).
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This moiety is seen in example compounds on the instant claims of pg 9-10.
claim 14
Regarding claim 14, Naito does not teach Ac comprises NH-Y-X.
Zhu teaches Ac can be glycine (e.g. comprises the structure of -NH-CH2-COOH) (claim 15), which satisfies the limitation of instant structure ADC-2, when combined with the teachings of Naito discussed in the rejection of claim 1.
claim 16
Regarding claim 16, Naito teaches deprotecting a protecting group can be performed, wherein reagents and conditions can be selected depending on the protecting group (pg 51, para 01236). Naito teaches a Lewis acid such as zinc chloride in methylene chloride (pg 53, para 1255) can be used in deprotection reactions. Because this claim could not be meaningfully interpreted as applicant did not describe what was being protected or with what protecting group, this teaching of Naito essentially encompassed the claimed limitation. See corresponding 112(b) rejection of this claim.
Kierzek teaches ZnBr2 can be used as a means of deprotecting the di-p-anisylphenylmethyl (DMT) protected alcohols using either nitromethane or methylene chloride as the solvent (pg 3761, para 1).
It would have been obvious to combine the teachings of Naito and Kierzek because both claim a deprotection reaction involving a zinc-based Lewis acid in combination with an aprotic solvent such a methylene chloride or nitromethane.
Claim 17
Regarding claim 17, Naito teaches generating the exemplary ADC via combining the antibody trastuzumab with the maleimide-containing drug-linker precursor (pg 249-250, para 2190), shown below.
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Naito does not give an exemplary synthesis featuring the exact structural features of formula III, but does claim all the structural features of the product as described in the rejection of claim 1.
Allowable Subject Matter
Claim 15 is drawn to a specific one-step synthetic process that was not found in the prior art.
The closest prior art is that of Naito, which achieves the same result using three steps as opposed to one step as instantly claimed. Naito teaches generating the methanesulfonic acid salt of Exatecan and adding it to glycolic acid to generate the precursor compound shown below (pg 89, para 1505).
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Naito teaches the methanesulfonic acid of Exatecan (MsOH*Exatecan) can be added to amino acid linkers to form the linker-Exatecan conjugate precursor, shown below (pg 96).
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Naito teaches the maleimide unit is added in a subsequent step, shown below (pg 96).
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Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA ANN ESSEX whose telephone number is 571-272-1103. The examiner can normally be reached Mon - Fri 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached on 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/
Supervisory Patent Examiner, Art Unit 1675
Prosecution Insights