DETAILED ACTION
1. Claims 1, 3-4, 6-17, 21-22, 24, and 29 are currently pending and under examination.
Priority
2. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 12/09/2020. It is noted, however, that applicant has not filed a certified copy of the CN202011424591.7 application as required by 37 CFR 1.55. Therefore, they are not granted priority or the effective filing date of the above application.
Priority is acknowledged and granted for PCT/CN2021/136419 and the effective filing date for the current claims is 12/08/2021.
Specification
3. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, for example on page 11, lines 12-14. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
4. Claim 4 is objected to because of the following informalities: claim 4 recites “wherein the said antibody.” Please correct to cite “the antibody” or “said antibody.” Appropriate correction is required.
Claim Interpretation
5. The examiner’s broadest reasonable interpretation of the claims is set forth below.
Claim 1 recites:
“An antibody or an antigen-binding fragment specifically binding to MSLN, comprising: a CDR1, a CDR2, and a CDR3, wherein amino acid sequences of the CDR1, the CDR2, and the CDR3 are:
(1) the CDR1, according to the KABAT, Chothia, or IMGT numbering scheme, respectively comprises a sequence set forth in SEQ ID NOs: 65, 101, and 137;
(2) the CDR2, according to the KABAT, Chothia, or IMGT numbering scheme, respectively comprises a sequence set forth in SEQ ID NOs: 66, 102, and 138;
(3) the CDR3, according to the KABAT, Chothia, or IMGT numbering scheme, respectively comprises a sequence set forth in SEQ ID NOs: 67, 103, and139.
The phrases “amino acid sequences of the CDR1, CDR2, and the CDR3” and “the CDR1..comprises a sequence set forth in SEQ ID NOs: 65, 101, and 137”, “the CDR2… comprises a sequence set forth in SEQ ID NOs: 66, 102, and 138”, and “the CDR3… comprises a sequence set forth in SEQ ID NOs: 67, 103, and 139” are reasonably interpreted as an antibody or an antigen-binding fragment specifically binding to MSLN, comprising a CDR1, CDR2, and CDR3, each CDR comprising any sequence found in the listed SEQ ID NOs, as few as two consecutive amino acids long.
Claim 4 recites:
“The antibody or the antigen binding fragment according to claim 1, wherein the said antibody or antigen-binding fragment comprises a sequence set forth in SEQ ID NO:33.”
The phrase “comprises a sequence set forth in SEQ ID NO:33” is reasonably interpreted as comprising any sequence found in SEQ ID NO:33 as few as two consecutive amino acids long.
Claim Rejections - 35 USC § 112
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.
6. Claims 1, 3-4, 6-17, 21-22, 24 and 29 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
Claim 1 is drawn to antibody or an antigen-binding fragment specifically binding to MSLN, comprising: a CDR1, a CDR2, and a CDR3, wherein amino acid sequences of the CDR1, the CDR2, and the CDR3 are:
(1) the CDR1, according to the KABAT, Clothia, or IMGT numbering scheme, respectively, comprises any sequence set forth in SEQ ID NOs: 65, 101, and 137 as few as two consecutive amino acids.
(2) the CDR2, according to the KABAT, Clothia, or IMGT numbering scheme, respectively, comprises any sequence set forth in SEQ ID NOs:66, 102, and 138 as few as two consecutive amino acids.
(3) the CDR3, according to the KABAT, Clothia, or IMGT numbering scheme, respectively, comprises any sequence set forth in SEQ ID NOs:67, 103, and 139, as few as two consecutive amino acids.
Dependent claims 4 and 6 recite the antibody comprises a partial sequence of Alpaca anti-MSLN nanobody NB149-95 VHH SEQ ID NO:33, where the antibody can comprise up to 20% sequence discrepancy from SEQ ID NO:33.
Dependent claim 9 recites the antibody or antigen-binding fragment is a full human antibody or a fragment thereof.
Dependent claims further recite a chimeric antigen receptor (CAR), multispecific antibody, immune effector cell, method of preparing an immune effector cell, and method for preventing/treating a tumor comprising the antibody of claim 1.
The claims identify the antibody by the functions of:
Binding to MSLN;
Binds to human MSLN with a dissociation constant (KD) not greater than 20 mM; and
Preventing and/or treating a tumor in a patient.
The claims identify the antibody by partial sequence structure encompassing as few as two consecutive amino acids from the claimed CDR 1-3 SEQ ID NOs, or comprising up to 20% sequence discrepancy from VHH SEQ ID NO:33.
Thus, the claims encompass a vast genus of antibody variants required to bind MSLN and treat/prevent a tumor in a patient.
The instant specification discloses producing single domain (VHH) antibodies in alpaca against human MSLN protein (Example 2) and isolated resulting antibodies listed in Table 21. The specification discloses anti-MSLN NB149-95 VHH SEQ ID NO:33 in Table 21 that binds to MSLN and comprises 100% of CDR1 SEQ ID NOs: 65, 101, and 137; 100% of CDR2 SEQ ID NOs:66, 102, and 138; and 100% of CDR3 SEQ ID NOs:67, 103, and 139. The instant specification fails to disclose variant antibodies comprising less than 100% of the three CDR SEQ ID NOs that function to bind MSLN. The instant specification does not disclose a single exemplary fully human antibody.
To provide adequate written description and evidence of possession of the claimed antibody genus, the instant specification can structurally describe representative antibody variants that function to bind MSLN, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
In this case, the only factor present in the claims is a recitation of the antibody function listed above, binding to MSLN and treating/preventing a tumor, and a partial sequence structure as stated above. The instant specification fails to describe structural features common to the members of the antibody genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative antibody variant sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than for VHH SEQ ID NO:33 comprising CDR1 SEQ ID NO:65, 101, or 137; CDR2 SEQ ID NO:66, 102, or 138; and CDR3 SEQ ID NO:67, 103, or 139, the specification fails to provide the CDR1, CDR2, and CDR3 structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antibody sequence variants for the genus of antibodies that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed antibodies and to practice the claimed methods.
The claims broadly encompass any antibody sequence variant having as few as two consecutive amino acids from CDR1 SEQ ID NO:65, 101, or 137; CDR2 SEQ ID NO:66, 102, or 138; and CDR3 SEQ ID NO:67, 103, or 139; or comprising up to a 20% sequence discrepancy from VHH SEQ ID NO:33, that function to bind MSLN. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the CDRs that can be altered and still maintain MSLN binding function Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single parental anti-MSLN NB149-95 VHH SEQ ID NO:33 to the structure of any variants required to bind MSLN as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
With regard to claim 9 reciting a full human antibody, the instant specification fails to provide a single exemplary human antibody because the specification discloses only antibodies produced in alpaca that do not comprise any human sequences. Therefore, the specification fails to provide a single exemplary species of a full human antibody and fails to disclose human antibody sequences critical to the function of binding MSLN.
Although Applicants may argue that it is possible to screen for antibodies that bind MSLN and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The MSLN antigen provides no information about the structure of an antibody that binds to it.
Given the lack of representative examples to support the full scope of the claimed variant antibodies, and lack of reasonable structure-function correlation with regards to the unknown variable sequences in the CDRs that provide MSLN-binding function and tumor -treating function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibody variants that bind MSLN and comprise as few as two defined consecutive amino acids in each CDR 1-3 SEQ ID NO claimed that is required to practice the claimed invention.
Examiner Suggestion:
Amend claim 1 to recite:
An antibody or an antigen-binding fragment specifically binding to MSLN, comprising a CDR1, a CDR2, and a CDR3, wherein:
(1) the CDR1 comprises the sequence as set forth in SEQ ID NO: 65, 101, or 137, according to the KABAT, Clothia, or IMGT numbering scheme, respectively;
(2) the CDR2 comprises the sequence as set forth in SEQ ID NO: 66, 102, or 138 according to the KABAT, Clothia, or IMGT numbering scheme, respectively; and
(3) the CDR3 comprises the sequence as set forth in SEQ ID NO:67, 103, or 139, according to the KABAT, Clothia, or IMGT numbering scheme, respectively.
Amend claim 4 to recite:
The antibody or the antigen binding fragment according to claim 1, wherein the antibody or antigen-binding fragment comprises the sequence set forth in SEQ ID NO:33.
Cancel claims 3 and 6.
7. Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claim is drawn to the anti-MSLN antibody or antigen binding fragment that is a fully human antibody.
The specification discloses producing the claimed antibodies alpacas, therefore the CDR sequences are camelid. (See Example 2, pg. 28).
Given the claimed antibody sequences are camelid, they are not enabled to be human.
Examiner suggestion: Delete the phrase “(3) a full human antibody or a fragment thereof” from claim 9.
8. Claim 24 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a tumor in a patient in need thereof, does not reasonably provide enablement for a method of preventing a tumor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims as currently constituted encompass methods of preventing cancer.
The instant specification does not demonstrate that the claimed anti-MSLN antibodies prevent cancer.
A search of relevant art does not support that anti-MSLN antibodies binding to cells expressing MSLN can prevent cancer. For example, US 2017/0267755, Scholler, cited below, demonstrates that anti-MSLN antibodies and associated fragments that bind to MSLN on cell surfaces can be used for diagnostic, prognostic, and therapeutic purposes in treating cancer but provides no evidence of preventing cancer (See Scholler, More Detailed/Experimental Embodiments, pgs. 9-14).
One cannot extrapolate the disclosure of the specification to the scope of the claims because the specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent cancer. Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to particular types of cancer or have had cancer. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and Iink those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. All of this underscores the criticality of providing workable examples which are not disclosed in the specification. A high quantity of experimentation would be required to determine if and what cancers the claimed anti-MSLN antibody or antigen-binding fragment could prevent.
Reasonable correlation must exist between the scope of the claims and scope of enablement set forth, and it cannot be reasonably predicted that the claimed immune cell comprising the claimed antibody will predictably function to prevent cancer as claimed.
Therefore, in view of the state of the art, the quantity of experimentation necessary, the breadth of the claims, lack of guidance in the specification, and the absence of working examples, it would require undue experimentation for one skilled in the art to practice the invention as claimed.
Examiner Suggestion: Amend claim 24:
A method for treating a tumor in a patient in need thereof, the methods comprising: administering to the patient an effective amount of the antibody or the antigen-binding fragment according to claim 1.
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.
9. Claims 8 and 29 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.
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, claims 8 recites the broad recitation “wherein the antibody or antigen-binding fragment comprises or does not comprise an antibody heavy chain constant region;” and the claim also recites, “optionally, the antibody heavy chain constant region,” which is the narrower statement of the range/limitation.
Dependent claim 29 further recites, “wherein the antibody or the antigen-binding fragment is a single-domain antibody or a heavy-chain antibody” which is a further narrower statement of the limitation from claim 8.
The claims 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.
10. Claim 22 is 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. Specifically, claim 22 recites “and optionally, an additional antineoplastic agent.” This claim is indefinite because by using “and” along with “optionally” it is unclear whether the additional antineoplastic agent is required or not required.
Prior Art
11. The closest prior art made of record but not relied upon is Wang (CA2996060 A1, published 3/2/2017). Wang discloses antibodies or antigen-binding fragments that binds to mesothelin comprising CDR regions. However, Wang does not disclose the amino acid sequences that correspond to SEQ ID NOs: 65, 66, 67, 101, 102, 103, 137, 138, 139, or at least 80% of SEQ ID NO:33.
The SEQ ID NOs represented above are compared to the SEQ ID NOs of Wang as shown in the table below.
Claimed Amino Acid Sequences
Wang’s disclosed Amino Acid Sequences
CDR1
ANYMG (SEQ ID NO: 65)
ESGFSAN (SEQ ID NO: 101, 137)
GDTVSSDSAA WN (SEQ ID NO: 54) Wang pg. 19
GYTFTSYYMH (SEQ ID NO: 60) Wang pg. 20
CDR2
TINRFGSTNYADSVKG (SEQ ID NO: 66)
NRFGS (SEQ ID NO: 102)
YINRFGST (SEQ ID NO: 138)
RTYYRSKWFNDY A VSVKG (SEQ ID NO: 55) Wang, pg. 19
IINPSGGSTSYAQKFQG (SEQ ID NO: 61) Wang, pg. 20
CDR3
MRPGNWY (SEQ ID NO: 67)
MRPGNWY (SEQ ID NO: 103)
RIMRPGNWY (SEQ ID NO: 139)
SNSYYYYAMDV (SEQ ID NO: 56) Wang, pg. 19
SRSGTTVVNHDAFDI (SEQ ID NO: 62)
Full VHH
QVQLVESGGGLVQAGGSL
RLSCTASESGFSANYMGW
YRQEAPGKERELVATINRF
GSTNYADSVKGRFTISRDN
AKNTVYLQMNSLKSEDTGV
YYCRIMRPGNWYWGQGTQ
VTVSS (SEQ ID NO: 33)
QVQLEQSGLGLVKPSQTL
SLTCAISGDTVSSDSAAWN
WIRQSPSRGLEWLGRTYY
RSKWFNDYAVSVKGRITIN
SDTSKNQFSLQLNSVTPED
TAVYYCARSNSYYYYAMDV
WGQGTLVTVSS (SEQ ID NO: 6 AAs 1-123) Wang, pg. 19
QMQLVQSGAEVKKPGASVK
VSCKASGYTFTSYYMHWVR
QAPGQGLEWMGIINPSGGST
SYAQKFQGRVTMTRDTSTST
VYMELSSLRSEDTAVYYCAS
S RSGTTVVNHDAFDIWGKGT
TVTVSS (SEQ ID NO: 8 AAs 1-124) Wang, pg. 19
Conclusion
12. Claims 1, 3-4, 6-17, 21-22, 24, and 29 are rejected.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LINDSAY DUNN whose telephone number is (571)272-5825. The examiner can normally be reached Monday-Friday 8-4:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LINDSAY DUNN/Examiner, Art Unit 1644
/Laura B Goddard/Primary Examiner, Art Unit 1642