DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s election of the species of SEQ ID NOs: 18, 59, and 100 for CDR-H1-3 and SEQ ID NO:141 in the reply filed on July 15, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-19 are pending and currently under consideration as they read on the elected species.
3. The drawing FIG. 1 filed on June 16, 2023 is not legible. Applicant is required to resubmit FIG. 1 for clarity.
4. 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.
5. Claims 1-19 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) Claims 1 and 3-19 are indefinite in the recitation of the 90%, 95%, or 99% sequence identity to the recited CHR-H1-3 SEQ ID NOs because the metes and bounds are unclear. For example, CDR-H1 of SEQ ID NO:1 consists of eight amino acids GSIYDFYS. A sequence that is 90%identical to these eight amino acid sequences would mathematically permit only 0.8 amino acid difference (8x10%=0.8).
Because a fractional amino acid substitution is impossible, no sequence with an integer number of amino acid changes can satisfy exactly 90% identity. An eight amino acid sequence can only differ by either zero amino acids (100% identity) or one amino acid (87.5% identity), making a 90% identity threshold mathematically unattainable.
B) Claims 1-19 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the anti-HCMV antibodies with different CDRs is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Each of the antibodies has unique antigen binding domain including CDRs sequences and heavy chain variable domain sequences which are not shared by other antibodies with CDRs. The elected antibody having CDRs set forth in claim 2(18) and heavy chain variable region of SEQ ID NO:141 does not share the CDRs with the other antibodies.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
6. 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.
7. Claims 1 and 3-19 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1 and 3-19 are drawn to a mesothelin (MSLN) binding polypeptide comprising an Ig heavy chain variable domain comprising a CDR-H1, CDR-H2, and CDR-H3, each comprises a sequence having at least 90%, 95%, 99% sequence identity to the recited SEQ ID NOs. Dependent claim 3 further recites a heavy chain variable domain comprising an amino acid sequence having at least 90%, 95%, 99% sequence identity to the recited amino acid sequences. Dependent claims 6-12 further recites CAR cell comprising a CAR comprising the MSLN binding polypeptide. Dependent claims 14-19 further recite a method of treating a cancer by administering the CAR.
The specification discloses specific single domain MLSN binding polypeptides each comprises specific amino acid sequences for CDR-H1-3 (e.g. see pages 34 and 35 of the specification as-filed). The specification discloses several anti-MSLN CAR-T cell lines showed cytotoxic efficacy against pancreatic cancer cells and one anti-MSLN CAR T-cell line B4T2-002 showed clearance of the xenograft breast cancer cells, non-small cell lung cancer, and gastric cancer in mouse model (e.g. see Example 2).
There is insufficient written description in the specification as-filed of the MSLN binding polypeptides as recited in the instant claims.
The claims recite a MSLN binding polypeptide comprising three CDR-H1-3, each having at least 90%, 95%, or 99% sequence identity to the recited SEQ ID NOs as part of the invention without providing which amino acids can be mutated for the function of MSLN binding. The claims also encompass mix and match CDR H1 among any SEQ ID NOs: 1-41, CDR-H2 among any of SEQ ID NOs: 42-82, and CDR-H3 among any of SEQ ID NOs: 83-123.
The specification discloses specific single domain MSLN binding proteins having specific CDRs (e.g. see pages 34-37 of the specification as-filed).
The genus of the MSLN binding proteins is therefore extremely large. Applicant has disclosed only specific MSLN binding protein having specific CDR-H1-3. Thus, Applicant has disclosed only a limited species of the MSLN binding polypeptides, namely the single domain MSLN binding protein having amino acid sequences for the three CDRs. The claimed MSLN binding polypeptides lack a common structure essential for their function of MSLN binding and the claims do not require any particular structure basis or testable functions be shared by the instant polypeptides.
It was known in the art that VHH engineering can be unpredictable. For example, De Genst et al. (Developmental and Comparative Immunology 30(2006) 187-198) teach that the VHH amino acid sequences resembles closely to that of a human VH of family III, with notable differences in its FR2 and CDRs in that the hydrophobic amino acid residues in the human VH FR2 region (e.g. the highly conserved Val42) was replaced with more hydrophilic resides in VHH (Phe42) and the conserved hydrophobic amino acid residues in the VHH FR2 region are important in maintaining the solubility of the isolated VHH domain (e.g. see page 188).
De Genst et al. further teach that since the three antigen binding loops provided by a VL are absent in the antigen-binding site in the VHH, the three CDRs of the VHH are critical for antigen binding specificity and affinity and that cloning VHH antibody (e.g. by phage display or camelizing CDR3 by using a synthetic library) can be disadvantageous since lower affinity binders are often obtained that need additional mutagenesis steps (e.g. see right column on page 188 and left column on page 196).
Tereshko et al. (Protein Science. 2008, 17:1175-1187), in engineering VHH that binds RNase from yeast surface display system, teach that only a small fraction of the library was both expression and antigen-binding, indicating that some of the mutations or combinations thereof are detrimental to the VHH antigen binding and stability (e.g. see pages 1176-1178).
Deschacht et al. (The Journal of Immunology, 2010, 184:5696-5704) teach that the llama H chain antibody (HCAbs) differs from the VH domain of classical antibodies only by a few crucial substitutions of the amino acid normally involved in VL parings with hallmark residues located in FR2 with additional key residues located in CDR loops for maintaining antigen binding and soluble behavior and the inherent hypervariable character (in length and sequence of the CDR regions precludes identification of the critical residues (e.g. see pages 5696 and 5702-5703).
Sircar et al. (The Journal of Immunology 2011, 186:6357-6367) teach that the CDRs of the VHH antibody adopt diverse conformations not classifiable by established canonical rules and thus, VHH structures with biological relevant conformations of the unique CDR loops are required to understand VHH-antigen interaction (e.g. see pages 6357-6358).
Further, while it is not required that all potential embodiments be disclosed, the written description doctrine requires that sufficient representing species be disclosed in order to support the entire genus. Rather than simply listing various embodiments, the usual approach is to also describe common structural features of the species. See Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1997) and Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
In Abbvie Deutschland Gmbh & Co KG, Abbvie Bioresearch Center, Inc.,and Abbvie Biotechnolo~, Ltd., v. Janssen Biotech In. And Centocor Biologics,LLC, Case No. 2013-1338 and 2013- 1346, C.A.Fed. ("Abbvie"), the Federal Circuit reiterates the inherent unpredictability of protein engineering in Abbvie. For example, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 ("[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology."); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation. Instead, AbbVie used a trial and error approach to modify individual amino acids in order to improve the IL-12 binding affinity.”
In Novozymes A/S et al. v. Dupont Nutrition Biosciences APS et al., 2013 WL3779376, Case No. 2012-1433, C.A.Fed. (Wis.), the court states:
“The effects of any given mutation or combination of mutations in a variant can differ depending on the position(s) modified and the specific mutation implemented at each position. Some mutations may have no discernible effect on enzyme function, somemay lead to varying degrees of instability or functional impairment, and some may actually improve enzyme activity or impart other desirable properties, such as improved stability at high temperatures.” Page 5.
Here, it does not appear based upon the limited disclosure of full length MSLN binding polypeptide with specific amino acid sequences for all three CDRs alone that applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the limited number of species disclosed and the extensive variation permitted within the genus of MSLN binding polypeptides.
The disclosure of the species of MSLN binding polypeptides having specific CDR-H1-3 amino acids sequences not sufficient support an entire genus MSLN binding polypeptides as recited that encompass mutations in unspecific positions within the CDRs as well as mix CDRs from different polypeptide together for the MSLN binding.
The common structural elements essential to the common utility of the MSLN binding polypeptide requires a full length VHH with minimally defined amino acid sequences of three CDRs to be associated with FR sequences commonly known to a skilled artisan.
“Adequate written description 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.” Regents of the University of California v. Eli Lilly and Co. 43 USPQ2d 1398 (Fed. Cir. 1997).
The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter of the claim. Id. 43 USPQ2d at 1406.
In the absence of disclosure of relevant, identifying characteristics of the MSLN binding polypeptide (namely the amino acid sequences of CDR1, CDR2 and CDR3), there is insufficient written disclosure under 35 U.S.C. 112, first paragraph for the claimed MSLN binding polypeptide. Logically, if applicant was not in possession of the MSLN polypeptide which is being administered, applicant also was not in possession of the nucleic acid encoding the polypeptide, vector, host cell, CAR, CAT-T cell, and the methods of administering such reagents at the time the instant application was filed.
8. The MSLN binding polypeptide comprising an immunoglobulin heavy chain variable domain comprising CDR-H1 of SEQ ID NO:18, CDR-H2 of SEQ ID NO:59, and CHR-H3 of SEQ ID NO:100 and the MSLN binding polypeptide comprising amino acid sequence of SEQ ID NO:141 are free of the prior art.
9. No claim is allowed.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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