DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to a response filed 10/27/2025.
Claims 1-7, 19, 20, 32, 34, 36-40, 44, 49, 55, 66, 67, 72, 73, 86-91, 93 and 97-101 are pending.
This application is a continuation of U.S. provisional applications 63/287,394 filed 12/8/2021, 63/288,479 filed 12/10/2021 and 63/421,052 filed 10/31/2022.
Election/Restrictions
Applicant's election without traverse of Group I (claims 1-7, 19, 20, 32, 34, 36-40, 44, 49, 55, 66, 67, 72, 73, 90 and 99) drawn to an antibody that binds to CALR in the reply filed on 10/27/2025 is acknowledged.
Applicants elect VH- SEQ ID NO:191, VL- SEQ ID NO:315, VH CDR1- SEQ ID NO:1, VH CDR2- SEQ ID NO:95, VH CDR3- SEQ ID NO:18, VL CDR1-SEQ ID NO:30, VL CDR2-SEQ ID NO:55, VL CDR3- SEQ ID NO: 71. Based on the species election, claims 32-40, 86-89, 91, 93, 97, 98, 100 and 101 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Per MPEP 821.04(a), rejoinder occurs once allowable subject matter is identified.
Therefore, claims 1-7, 19, 20, 44, 49, 55, 66, 67, 72, 73, 90 and 99 are under examination.
Information Disclosure Statement
Information disclosure statements filed 3/20/23. 8/15/23 and 9/24/2024 have been identified and the documents considered. The corresponding signed and initialed PTO Form 1449 has been mailed with this action. Initials indicate that the document has been considered even if the reference is lined through. In the case that only an English abstract was identified, this is indicated.
Sequence Compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below or on the attached Notice To Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures.
Specifically, the first listing for VH CDR1 in Table 2, on page 106 requires a SEQ ID NO: according to the rules of 26.2 contain sequences that are not identified by sequence identifier numbers. Rule 26.2 identifies a variable listing for an amino acid sequence as “specifically defined” residue other than those represented by “Xaa” or X that represents any choice. In this case, X stands for limited choices-
PNG
media_image1.png
121
200
media_image1.png
Greyscale
The same is true for the listings on page 107 that lack SEQ ID NO:s. If the sequences can be found in the sequence listing it would be remedial to insert the appropriate SEQ ID NO:s. If not, a substitute paper copy of the “Sequence Listing”, as well as an amendment directing its entry into the specification, CRF and letter stating that the contents of the sequence listing and the CRF are the same and contain no new matter is required. The nature of the non-compliance did not preclude the examination on the merits of the instant application, the results of which follow.
Claim Objections
Claims 2, 5 and 6 are objected to because of the following informalities: in claim 2, for proper formatting, reference to “any one of SEQ ID NO:s” should be preceded by –of any one of the amino acid sequences of SEQ ID NO:s--. This is true of claim 5 and claim 6. Appropriate correction is required.
Claim Rejections - 35 USC § 112, second paragraph
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 1-7, 19 and 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.
Claim 1 provides reference sequences from which CDR sequences are obtained. However, they do not all conform to the SEQ ID NO: sequences provided Claim 1 defines VH CDR2 as the VH CDR2 comprises the amino acid sequence X6X7X8PX9XoX11X12X13X14YAX15X16X17X18G (SEQ ID NO:97), wherein X6 is L or G; wherein X7 is V, F, or I; wherein X8 is D or I; wherein X9 is E, D, or I; wherein X10 is D, G, F, A, S, or E; wherein X11 is G or A; wherein X12 is E or T; wherein X13 is T or A; wherein X14 is I, M, or N; wherein X15 is E or Q; wherein X16 is K or R; wherein X17 is F or L; and wherein X18 is R or Q.
However, the sequences depending thereof do not follow this pattern.
Looking at elected SEQ ID NO:95 as well as all of the claimed sequences, there is a discrepancy at X9 is E, D, or I.
GFDPDDAETMYAEKFQG.
But also SEQ ID NO:17 does not conform at all.
HIWWDDDKYY NPYLKN
There are similar issues with SEQ ID NO:25 which does not fit the scheme required in claim 1.
SAYGSTYGY
This makes unclear the metes and bounds of the CDR sequences.
Claim 3 is rejected to for recitation that the CDRs are set forth in Tables 1-2. Where possible, claims are to be complete in themselves and as such the claims are objected to because they reference table 1-2 (see MPEP 2173.05(s)). It would be remedial to insert the contents of table 1-2 into claim 3. It does appear that claim 4 encompasses all of this data.
Claim 20 is rejected to for recitation that the heavy and the light chains are set forth in Tables 4-5. Where possible, claims are to be complete in themselves and as such the claims are objected to because they reference table 4-5. (see MPEP 2173.05(s)). It would be remedial to insert the contents of table 4-5 into claim 20. It does appear that claim 19 encompasses all of this data.
Claim Rejections - 35 USC § 112 ¶4 rejection
The following is a quotation of the fourth paragraph of 35 U.S.C. 112:
Subject to the [fifth paragraph of 35 U.S.C. 112 prohibiting improper multiple dependent claims], 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.
Claims 2-7, 19 and 20 rejected under 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 1 defines VH CDR2 as the VH CDR2 comprises the amino acid sequence X6X7X8PX9XoX11X12X13X14YAX15X16X17X18G (SEQ ID NO:97), wherein X6 is L or G; wherein X7 is V, F, or I; wherein X8 is D or I; wherein X9 is E, D, or I; wherein X10 is D, G, F, A, S, or E; wherein X11 is G or A; wherein X12 is E or T; wherein X13 is T or A; wherein X14 is I, M, or N; wherein X15 is E or Q; wherein X16 is K or R; wherein X17 is F or L; and wherein X18 is R or Q.
However, the sequences depending thereof do not follow this pattern.
Looking at elected SEQ ID NO:95 as well as all of the claimed sequences, there is a discrepancy at X9 is E, D, or I.
GFDPDDAETMYAEKFQG.
But also SEQ ID NO:17 does not conform at all.
HIWWDDDKYY NPYLKN
There are similar issues with SEQ ID NO:25 which does not fit the scheme required in claim 1.
SAYGSTYGY
Applicants should go through CDR1, 2 and 3 for VL and ensure all meet the formula. Even though not elected, any claims comprising CDR2 should be inspected.
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 § 112, first paragraph
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.
Claims 5, 44, 49, 55, 66, 67, 72 and 73 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.
The disclosure states that the invention is directed at developing anti-mutCALR antibodies for treating or diagnosing myeloproliferative neoplasms.
[0003] Calreticulin (CALR) is a highly conserved chaperone protein that resides primarily in the endoplasmic reticulum and is involved in a variety of cellular processes including protein folding, calcium homeostasis, cell adhesion, and integrin signaling. CALR is also found in the nucleus, suggesting that it may have a role in transcription regulation. Mutations in the gene for CALR have been identified in patients with myeloproliferative neoplasms.
Antibodies are made up of a number of components. The VH and VL fragments comprise CDR1, 2 and 3. These are part of heavy chains and light chains and perform antigen binding. The claims recite a large number of components as well as combination of the components in antibodies. Claim 5 delineates VH and VL as sequences with 80% relationship with a number of sequences. For VH is it SEQ ID NO:165-181 and VL 236-304 and 306-318. While this is large number of sequences with potential overlap, VH and VL function as prescribed in the antibody have specific functions. In this case, the sequences must bind to CALR. Hence, the claims require a function and a broad number of variant sequences wherein it is not clear how to identify those that will perform the function from those that do not. The antibodies are broadly described and claimed in such a manner to comprise a large genus of molecules. However, claiming variants of these VH and VL sequences expands this genus into molecules claimed but not described.
Claims 44, 49, 55, 66, 67, 72 and 73 claim antibodies solely in terms of their function or epitope binding properties. While many antibodies are claimed, it is not clear what the structure-function nexus is for each of the properties. The disclosure teaches a number of CDR1, CDR2 and CDR3 for VH and VL and from these prepares a number of VL and VH fragments. As well, the disclosure teaches a number of Heavy chains and light chains. Some of these are combined to form antibodies that are tested and these are claimed clonally in the functional assays. To this end, it is not possible to calculate the structure-function nexus of the components.
For example, claim 49 recites an antibody that binds to mutCALR wherein the antibody has modulated FC effector function. This is the region of the antibody that mediates the effect of antigen binding in the Fab region. To this end, the disclosure teaches a single mutation in “a heavy chain” of clones 6, 15 and 17. The nature of the starting heavy chain is unknown but the mutation is defined. It is but a single mutation.
[0678] Mutations were introduced into three of the identified clones (clones 6, 15, and 17) to generate 161 unique mutant clones (clones 55-215). The amino acid sequences of the six CDRs for each of the mutant clones are shown in Table 2. Light chain and heavy chain sequences of the parental clones (clones 6, 15, and 17) and mutant clones (clones 55-215) are shown in Table 5. One such mutation to the heavy chain, N297A, resulted in Fc effector function “null” mutants, where the Fc effector function, particularly ADCC, was eliminated or substantially eliminated. As can be seen from the activity data in the Examples, those antibodies with N297A Fc effector null mutations have a generally increased binding affinity for mutCALR than those antibodies without an Fc effector null mutation.
Hence, the genus is not well described except for the mutation that alters the Fc effector function.
For some functions such as claim 44 drawn to an antibody that binds to human mutant calreticulin (CALR), wherein the antibody:
inhibits one or more signaling pathways downstream of thrombopoietin receptor (MPL) in a cell expressing human mutant CALR;
inhibits oncogenic cell proliferation in a cell expressing human mutant CALR;
inhibits dimerization of MPL in a cell expressing human mutant CALR; and/or
inhibits binding of MPL to human mutant CALR.
The disclosure shows some clones (combinations of specific CDR1, 23, and VH and VL as well as heavy chain and light chains) that mediate inhibition of pSTAT5 and cell proliferation (see figure 1 and 2). But, it is unclear what common attributes or features are responsible for these functions. As to epitope binding, the description is much more limited than the claims provide by reciting an antibody in terms of its epitope binding.
FIG. 16C shows the CDR composition of the Fab fragment. Bold font denotes amino acids that contribute to the epitope recognition in mutant CalR. CCG numbering scheme was used for defining the CDR in MOE
PNG
media_image2.png
357
562
media_image2.png
Greyscale
Hence, one would expect the bolded amino acids to be required in the antibody for the epitope used in this experimental for binding.
Therefore, the claims are drawn to an extremely large genus of antibodies wherein the disclosure does not present identifying relevant characteristics of which structures are required nor does it provide a structural-functional relationship for the functions recited in claims 5, 44, 49, 55, 66, 67, 72 and 73. The written description requirement for genus claims may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with known or disclosed correlations between function and structure, or by a combination of such characteristics sufficient to show that the applicant was in possession of the claimed genus.
Closest Prior Art
A thorough search of the art could not be made due to the inconsistent sequence information as set forth above. However, SEQ ID NO:1 as CDR1 was identified in the art. It was not found in connection to the CDR2 as claimed. The CDR1 sequences was found in Table D1, page 53 of US 20230056252 Baca et al.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIA MARVICH whose telephone number is (571)272-0774. The examiner can normally be reached 8 am - 5 pm.
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, Maria Leavitt can be reached at 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MARIA MARVICH/Primary Examiner, Art Unit 1634