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 .
DETAILED ACTION
Claims 6-10 are pending in the instant application.
Priority
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C.
119(a)-(d) prior to declaration of an interference, a certified English translation of the
foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and
41.202(e).
Failure to provide a certified translation may result in no benefit being accorded
for the non-English application. The effective priority date is the filing date of
PCT/CN2021/137352 filed on 12/13/2021 in the absence of a certified translation of
CN202011516850.9 filed on 12/21/2020.
.
Claim Interpretation
Regarding claim 8, the claim is a product by process claim.
Objections to the Claims
Claim 9-10 are objected to because of the following informalities:
Claim 9 contain periods after the numbered steps and should be changed to semicolons throughout all steps. MPEP 608.01(m) states periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i).
Claim 9 is grammatically incorrect and states wherein the method… “comprising the following steps” as opposed to ---comprises the following steps--- .
Claim 10 is grammatically incorrect and states “the preparation of drug with enhanced immune effect function of antibody” as opposed to ---the preparation of a drug with enhanced immune effect function of an antibody--- .
Appropriate correction is required.
Objections to the Abstract
The abstract of the disclosure is objected to because the abstract contains a sequence listing. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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 9-10 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 9 recites the limitation "the antibody is selected from any one antibody of claim 6" in line 5. There is insufficient antecedent basis for this limitation in the claim.
The antibody species are further defined in claim 7 not claim 6.
Claim 9 does not include a conjunction of ---and--- or ---or--- that indicates whether all wherein clauses are required or just one. Thus, the claim is indefinite and the metes and bounds are unclear. Claim 10, further depends on claim 9 and is indefinite.
Claim 10, states adding a thiol containing reducing agent TCEP, but TCEP does not contain thiols and is a phosphine-based reducing agent.
Claim Rejections – 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 and 10 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 7 claims the monoclonal antibody as “including but not limited to” a list of antibodies to separate antibody targets. Thus, the claim is not further narrowed to any antibody that is not a monoclonal antibody which was already required by the parent claim 6.
Claim 10 claims the method of claim 9, but claim 9 is a claim to a pharmaceutical composition not a method. Recitation of the “use” of a pharmaceutical composition in claim 9 in the preparation of a drug is not a method claim. Thus, claim 10 is an improper dependent claim of claim 9 that fails to further limit the claim.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections – 35 USC § 103
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.
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 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019127346 ( Wu Z et al. IDS reference ) and Maass KF et al. (J Pharm Sci. 2015 104(12):4409–4416) and evidenced by WO 2019/127346 translated ( Wu Z et al.).
‘346 translated taught bifunctional molecules that specifically target tumor cells and can effectively recruit anti-Rha antibodies to achieve different degrees of killing of tumor cells (20%-90%) by mediating CDC or ADCC (page 7, [0076]).
‘346 translated taught an anti-HER2 nanobody, C7b, conjugated to rhamnose (Rha) in the antibody conjugates C7b-triEGRha and C7b-hexEGRha, wherein pharmaceutical compositions comprising C7b-triEGRha and C7b-hexEGRha could specifically bind cancer cells that expressed the HER2 target (page 11, [0122] and Fig. 5) and effectively induce ADCC and CDC to kill cancer cells (page 11, [0122-0126] and Fig 6A-B).
‘346 translated taught synthesis of C7b-triEGRha and C7b-hexEGRha via sortase conjugation (page 11, [0117-0118]).
‘346 translated taught conjugation of Rha to the GGG via a Rha-PEG-primary amine reactive moiety wherein n = 2 (page 10, [0109-0112])
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‘346 did not teach: A) a SMCC linked Rha hapten conjugate, but this is obvious in view of Maass.
Maass taught a method of preparing an anti-HER2 antibody drug conjugate pharmaceutical composition via cysteine conjugation to produce a Trastuzumab-Doxorubicin Conjugate, Tras-Dox (page 4411, right column, second paragraph). Maass taught a method of producing Tras-Dox with Doxorubicin–SMCC, wherein Doxorubicin–SMCC was produced by adding succinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (SMCC), doxorubicin, diisoprpylethylamine (DIPEA), and dimethylformamide (DMF) together to conjugate the primary amine of doxorubicin with SMCC (page 4411, left to right bridging paragraph and Scheme 1.)
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Maass taught the conjugate Tras-Dox effectively bound cancer cells that expressed HER2 (Supplemental page 1, supplemental Table 1 ).
Regarding claims 6-9, it would have been obvious for a person having ordinary skill in the art to take the Rha-PEG-primary amine reactive moiety wherein n = 2
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of ‘346 in the pharmaceutical compositions comprising C7b-triEGRha and: A) exchange the sortase-GGG comprising linker antibody conjugation for a SMCC linker-cysteine anti-HER2 antibody conjugation, wherein
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is added to SMCC in DIPEA and DMF in view of Maass.
This is obvious because: A) Maass taught an effective method of preparing an anti-HER2 antibody drug conjugate via cysteine conjugation to produce a Trastuzumab-Doxorubicin Conjugate, Tras-Dox, wherein SMCC, doxorubicin, DIPEA, and DMF successfully conjugated the primary amine of doxorubicin with SMCC to produce a conjugate Tras-Dox that effectively bound cancer cells that expressed HER2.
There is a reasonable expectation of success because: A) Maass taught an effective method of preparing an anti-HER2 antibody drug conjugate via cysteine conjugation to produce a Trastuzumab-Doxorubicin Conjugate, Tras-Dox, wherein SMCC, doxorubicin, DIPEA, and DMF successfully conjugated the primary amine of doxorubicin with SMCC to produce a conjugate Tras-Dox that effectively bound cancer cells that expressed HER2. Thus, the SMCC linker allowed successful conjugation to the anti-HER2 antibody and effective delivery to cancer cells.
This would produce a pharmaceutical compositions comprising an anti-HER2 antibody conjugated to the rhamnose hapten derivative of
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(claims 6-7). This pharmaceutical composition comprising the anti-HER2 antibody rhamnose hapten derivative above could naturally be used in the preparation of a drug with enhanced immune effect function of an antibody (claim 9). The synthetic pathway to produce the anti-HER2 antibody rhamnose hapten derivative above of ‘346 and Maass is:
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and would produce the hapten derivative claimed in the product by process claimed in claim 8, wherein determination of patentability is based on the product itself as taught by MPEP 2113.
Claims 6-10 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/127346 ( Wu Z et al. IDS reference ) and Maass KF et al. (J Pharm Sci. 2015 104(12):4409–4416) as applied to claims 6-9 above, and further in view of WO 2018/112027 (Chuang S et al), US 2018/0258048 (Coburn CA et al.), Rohrer T et al. (ADC Review / Journal of Antibody-drug Conjugates – June 21, 2013. DOI: 10.14229/jadc.2013.06.21.001.), Thermo Scientific TCEP HCl (https://documents.thermofisher.com/TFS-Assets/LSG/manuals/MAN0011306_TCEP_HCl_UG.pdf 2013), and GoldBio (https://www.goldbio.com/blogs/articles/tcep-the-reducing-agent. 3/31/2020).
‘346 and Maass are described above.
‘346 did not teach: 1) desalting the antibody in sodium borate and adding TCEP for antibody hapten conjugation but this is obvious in view of ‘027, ‘048, Rohrer, Thermo, and GoldBio.
‘027 taught to prepare the antibody conjugate Rex-3, the maleimide linker-payload was conjugated to cetuximab via its cysteine residues, wherein: 1) cetuximab was treated with a solution comprising 10 mM TCEP and sodium borate; 2) purified via Ultrafiltration; 3) the antibody was conjugated with 10 molar equivalents of the dasatinib-1 then quenched with cysteine; and 4) ultrafiltered in pH 7.4 PBS buffer to give Rex-3.
‘048 taught synthesis of effective antibody benzazepine conjugates, wherein HER2-TLR8 benzazepine conjugates were active in the presence of PBMCs and cancer cells that express HER2, as measured by TNFα production (Fig. 1)
‘048 taught synthesis of effective antibody benzazepine conjugates, wherein; 1) desalting of an antibody was performed via centrifugal filtration to exchange the antibody into a reaction buffer; 2) TCEP was added to the reaction and incubated with gentle shaking; 3) after the reduction was complete, the maleimide containing Compound-Linker 2.1 was added and incubated followed by quenching with cysteine; and 4) centrifugal filtration was performed on the conjugate (page 179, [0659-0660]).
Rohrer taught naked antibody raw material which is typically frozen at -20°C is thawed and the storage buffer is exchanged (page 6, first paragraph). Rohrer taught buffer exchange is often required to alter the pH, salt concentration, and remove excipients used to improve storage stability in the bulk antibody solution which may hinder or alter the performance of the conjugation reaction (page 6, first paragraph).
Thermo taught because TCEP does not contain thiols, it does not have to be removed from solutions before performing reactions involving maleimide labeling or cross-linking reagents (page 2, compatible applications, option 1). Thermo taught in most situations, TCEP concentrations < 10-20mM are compatible with maleimide reaction chemistry (page 2, compatible applications, option 1).
GoldBio taught TCEP is light sensitive and tubes containing TCEP should be covered with foil, which would keep them in the dark (page 7, Note 3).
Regarding instant claim 10, it would have been obvious for a person having ordinary skill in the art to prepare the antibody conjugate of the pharmaceutical composition of an anti-HER2 antibody conjugated to the rhamnose hapten derivative of ‘346 and Maass above – by:
using the method of preparation of ‘027 of conjugating the maleimide linker-payload to the antibody via its cysteine residues, wherein: 1) an antibody was treated with a solution comprising 10 mM TCEP and sodium borate; 2) purified via Ultrafiltration; 3) the antibody was conjugated with 10 molar equivalents of the maleimide linker conjugate then quenched with cysteine; and 4) ultrafiltered in pH 7.4 PBS buffer to give Rex-3;
Further modifying the method of ‘027 above to 1) desalt the antibody into the buffer of the reaction buffer in view of ‘048 and Rohrer; 2a) add TCEP to the reaction buffer in a second step and incubate with gentle shaking to reduce the cysteines of the antibody in view of ‘048; 2b) perform the reducing in the dark in view of GoldBio; and 2c) Not remove TCEP via ultrafiltration prior to the maleimide antibody conjugation reaction by in view of Thermo.
This is obvious because:
A) ‘027 taught an effective method of conjugating a maleimide linker to an antibody via the cysteine residues;
B1) initially desalting the antibody into the buffer of the reaction buffer was performed by ’048 and Rohrer taught naked antibody raw material which is typically frozen at -20°C is thawed and the storage buffer is exchanged which is often required to alter the pH, salt concentration, and remove excipients used to improve storage stability in the bulk antibody solution which may hinder or alter the performance of the conjugation reaction;
B2a) addition of TCEP to the reaction buffer and incubation with gentle shaking to reduce the cysteines of the antibody was taught by ‘048 and was effective to reduce the antibody for maleimide conjugation to produce an antibody conjugate;
B2b) GoldBio taught TCEP is light sensitive and tubes containing TCEP should be covered with foil, which would keep them in the dark;
B2c) Thermo taught because TCEP does not contain thiols, it does not have to be removed from solutions before performing reactions involving maleimide labeling reagents, wherein in most situations, TCEP concentrations < 10-20mM are compatible with maleimide reaction chemistry. Further, ‘048 did not remove the TCEP before maleimide conjugation to produce an effective conjugation.
There is a reasonable expectation of success because:
A) ‘027 taught an effective method of conjugating a maleimide linker to an antibody via the cysteine residues;
B1) initially desalting the antibody into the buffer of the reaction buffer was performed by ’048 and Rohrer taught naked antibody raw material which is typically frozen at -20°C is thawed and the storage buffer is exchanged which is often required to alter the pH, salt concentration, and remove excipients used to improve storage stability in the bulk antibody solution which may hinder or alter the performance of the conjugation reaction;
B2a) addition of TCEP to the reaction buffer and incubation with gentle shaking to reduce the cysteines of the antibody was taught by ‘048 and was effective to reduce the antibody for maleimide conjugation to produce an antibody conjugate;
B2b) GoldBio taught TCEP is light sensitive and tubes containing TCEP should be covered with foil, which would keep them in the dark;
B2c) Thermo taught because TCEP does not contain thiols, it does not have to be removed from solutions before performing reactions involving maleimide labeling reagents, wherein in most situations, TCEP concentrations < 10-20mM are compatible with maleimide reaction chemistry. Further, ‘048 did not remove the TCEP before maleimide conjugation to produce an effective conjugation.
This would produce a method of preparing the antibody conjugate of the pharmaceutical composition of an anti-HER2 antibody conjugated to the rhamnose hapten derivative, wherein:
the anti-HER2 antibody is desalted into a reaction buffer comprising sodium borate;
TCEP is added to the reaction and placed in a tube covered with foil to perform under dark and shaking conditions;
after the reduction reaction is completed, the antibody is conjugated with 10 molar equivalents of the maleimide linker conjugate
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then quenched with cysteine;
the antibody conjugate is ultrafiltered which would remove excess small molecules and obtain the corresponding antibody conjugate.
Conclusion
Claims 6-10 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN J SKOKO III whose telephone number is (571)272-1107. The examiner can normally be reached M-F 8:30 - 5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Z 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.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643