DETAILED ACTION
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 .
Priority
The instant application is a 35 U.S.C. 371 national phase application, and claims
priority to, International Application No. PCT/CN2022/077787, filing date 02/25/2022.
This PCT application claims priority to Chinese Application Nos. PCTCN2021134907
(filed 12/02/2021) and CN202110213137.5 (filed 02/26/2021). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Applicant is notified that 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 applications PCTCN2021134907 (filed 12/02/2021) and CN202110213137.5 (filed 02/26/2021) 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.
Status of Application/Claims
The preliminary amendment, filed 08/25/2023, is acknowledged. Claims 1-2, 13-14, and 23-38 are canceled. Claims 3-12 and 15-22 are currently amended. Claims 3-12 and 15-22 are currently pending and are examined on the merits herein.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted 08/25/2023 has been fully considered by the examiner.
Drawings
The drawings are objected to because of poor resolution in the following figures:
Legends and X-axes: Figs.3a-3h and Fig.4
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the terms Megalign, Takara, Fortebio, Abcam, and Biolegend, which are trade names or marks used in commerce, have been noted in this application. The terms should be in all caps wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 10-11, 15-16, and 20-21 are objected to because of the following informalities:
Claim 10 recites, “The anti-NKp30 single domain antibody of claim 1, wherein it further comprises…” which should be corrected to, “The anti-NKp30 single domain antibody of claim 1, wherein the antibody further comprises…”.
Claim 11 recites, “The anti-NKp30 single domain antibody of claim 8, wherein the amino acid sequence of the immunoglobulin Fc region being as shown by SEQ ID NO: 116” which should be corrected to, “The anti-NKp30 single domain antibody of claim 8, wherein the amino acid sequence of the immunoglobulin Fc region comprises SEQ ID NO: 116”.
Claim 15 recites, “A multifunctional fusion protein comprising an anti-NKp30 single domain antibody…” which should be corrected to, “A multifunctional fusion protein comprising the anti-NKp30 single domain antibody…”.
Claim 16 recites, “The multifunctional fusion protein of claim 11, wherein it further comprises one or more…” which should be corrected to, “The multifunctional fusion protein of claim 11, wherein the protein further comprises one or more…”.
Claim 20 recites, “…further comprises one or more secondary antibody or antigen-binding portions thereof…” which should be corrected to, “…further comprises one or more secondary antibodies or antigen-binding portions thereof…”.
Claim 21 recites, “…wherein it further comprises a cytokine…” which should be corrected to, “…wherein the fusion protein further comprises a cytokine…”.
Appropriate correction is required.
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 3-12 and 15-22 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 3 recites “…an amino acid sequence having one or more (preferably 2 or 3) conserved amino acid mutations (preferably substitutions, insertions or deletions)…”. It is unclear whether the phrases “preferably 2 or 3” and “preferably substitutions, insertions or deletions” are merely examples or if these are required limitations. Further, inclusion of terms/phrases in parentheses renders the claim indefinite because it is unclear if the parenthetical terms/phrases are merely examples or required limitations. For further examination, the phrases are considered to not be required.
Claim 4 recites, “The anti-NKp30 single domain antibody of claim 1…”. Claim 1 has been canceled. For further examination, claim 4 is interpreted as, “The anti-NKp30 domain antibody of claim 3…”.
Claim 5 recites, “The anti-NKp30 single domain antibody of claim 1…”. Claim 1 has been canceled. For further examination, claim 5 is interpreted as, “The anti-NKp30 domain antibody of claim 3…”.
Claim 6 recites the limitation "the VHH" in line 2. There is insufficient antecedent basis for this limitation in the claim. Further, claim 6 recites, “The anti-NKp30 single domain antibody of claim 3…”. The first mention of “VHH” is in claim 5. For further examination, claim 6 is interpreted as, “The anti-NKp30 single domain antibody of claim 5…”.
Claim 7 recites the limitation "the VHH" in line 1. There is insufficient antecedent basis for this limitation in the claim. Further, claim 7 recites, “The anti-NKp30 single domain antibody of claim 4…”. The first mentions of “VHH” are in claims 5 and 6. For further examination, claim 7 is interpreted as, “The anti-NKp30 single domain antibody of claim 6…”.
Claim 8 recites the limitation "the VHH" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Further, claim 8 recites, “The anti-NKp30 single domain antibody of claim 4…”. The first mentions of “VHH” are in claims 5-7. For further examination, claim 8 is interpreted as, “The anti-NKp30 single domain antibody of claim 6…”.
Claim 9 recites, “The anti-NKp30 single domain antibody of claim 1…”. Claim 1 has been canceled. For further examination, claim 9 is interpreted as, “The anti-NKp30 domain antibody of claim 3…”.
Claim 10 recites, “The anti-NKp30 single domain antibody of claim 1…”. Claim 1 has been canceled. For further examination, claim 10 is interpreted as, “The anti-NKp30 domain antibody of claim 3…”.
Claim 11 recites the limitation "the immunoglobulin Fc region" in line 2. There is insufficient antecedent basis for this limitation in the claim as claim 11 is currently stated to depend on claims 8, 4, and 1. Further, claim 11 recites, “The anti-NKp30 single domain antibody of claim 8…”. The first mentions of “the immunoglobulin Fc region” is in claim 10. For further examination, claim 11 is interpreted as, “The anti-NKp30 single domain antibody of claim 10…”.
Claim 12 recites, “A nucleic acid molecule encoding the anti-NKp30 single domain antibody of any one of claims 1-9.” Claims 1 and 2 have been canceled. For further examination, claim 12 is interpreted as, “A nucleic acid molecule encoding the anti-NKp30 single domain antibody of any one of claims 3-11.”
Claim 15 recites, “A multifunctional fusion protein comprising an anti-NKp30 single domain antibody of any one of claims 1-9.” Claims 1 and 2 have been canceled. For further examination, claim 15 is interpreted as, “A multifunctional fusion protein comprising an anti-NKp30 single domain antibody of any one of claims 3-11.”
Claim 16 recites “the multifunctional fusion protein” in line 1. There is insufficient antecedent basis for this limitation in the claim as claim 16 is currently stated to depend on claims 1, 4, 8, and 11. Further, claim 16 recites, “The multifunctional fusion protein of claim 11…”. The first mention of “multifunctional fusion protein” is in claim 15. For further examination, claim 16 is interpreted as, “The multifunctional fusion protein of claim 15…”. Additionally, the term “other antigens” in claim 16 is a relative term which renders the claim indefinite. The term “other antigens” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For further examination, the term “other antigens” is interpreted to mean any “non-NKp30 antigen.”
Claim 17 recites “the multifunctional fusion protein” in line 1. There is insufficient antecedent basis for this limitation in the claim as claim 17 is currently stated to depend on claim 1-9 and 12. Further, claim 17 recites, “The multifunctional fusion protein of claim 12…”. The first mentions of “multifunctional fusion protein” are in claims 15 and 16. For further examination, claim 17 is interpreted as, “The multifunctional fusion protein of claim 16…”.
Claim 18 recites, “The multifunctional fusion protein of claim 13…”. Claim 13 has been canceled. For further examination, claim 18 is interpreted as, “The multifunctional fusion protein of claim 17…”.
Claim 19 recites “the multifunctional fusion protein” in line 1. There is insufficient antecedent basis for this limitation in the claim as claim 19 is currently stated to depend on claims 1-9 and 12. Further, claim 19 recites, “The multifunctional fusion protein of claim 12…”. The first mentions of “multifunctional fusion protein” are in claims 15 and 16. For further examination, claim 19 is interpreted as, “The multifunctional fusion protein of claim 16…”.
Claim 20 recites “the antigen binding the secondary antibody or antigen-binding portion thereof” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim as claim 20 is currently stated to depend on claims 1-9 and 15. The first mention of “secondary antibody or antigen-binding portions thereof” is in claim 16 which recites “one or more secondary antibody or antigen-binding portions thereof”. Further, claim 20 recites, “The multifunctional fusion protein of claim 15…”. The first mentions of “multifunctional fusion protein” are in claims 15-19. For further examination, claim 20 is interpreted as, “The multifunctional fusion protein of claim 19 wherein the one or more secondary antibodies or antigen-binding portions thereof binds an antigen selected from NKP30… and/or KIR”.
Claim 21 recites “the multifunctional fusion protein” in line 1. There is insufficient antecedent basis for this limitation in the claim as claim 21 is currently stated to depend on claims 1, 4, 8, and 11. Further, claim 21 recites, “The multifunctional fusion protein of claim 11…”. The first mention of “multifunctional fusion protein” is in claim 15. For further examination, claim 21 is interpreted as, “The multifunctional fusion protein of claim 15…”.
Claim 22 recites “the cytokine” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. The first mention of “cytokine” is in claim 21. Further, claim 22 recites, “The multifunctional fusion protein of claim 17…”. The first mentions of “multifunctional fusion protein” are in claims 15-21. For further examination, claim 16 is interpreted as, “The multifunctional fusion protein of claim 21…”.
Claim Rejections - 35 USC § 112(a)
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.
Claims 3, 5-6, 9-12, and 15-22 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. THIS IS A WRITTEN DESCRIPTION REJECTION.
Claims 3, 5-6, and 9-12 are drawn to an anti-NKp30 single domain antibody. Claims 5-6, 9-12 and 15-22 are dependent on claim 3. Claim 9 further limits the anti-NKp30 single domain antibody by the functional limitation of binding NKp30 at a KD of 20.1 nM or less. Claims 15-22 are further drawn to a multifunctional protein that comprises the anti-NKp30 single domain antibody of claim 3.
: Claim 3 is inclusive of a large genus of anti-NKp30 single domain antibodies that are recited to comprise complementary determining regions CDR1, CDR2, and CDR3 wherein each CDR is only required to have 80% identity to the recited sequences. Further, the recitation of claim 3 allows for every possible combination of CDR1/CDR2/CDR3 using all SEQ ID NOs recited in each of CDR1, CDR2, and CDR3. Additionally, claim 6 recites “VHH” that is only required to have 80% identity to the recited SEQ ID NOs and there is no indication that the claim is limited to variability in the non-CDR regions.
However, the written description in this case sets forth 46 structures for anti-NKp30 antibodies, and thus multifunctional fusion proteins comprising the 46 anti-NKp30 antibodies, in the specification. The specification does not disclose, and the art does not teach, the genus of antibodies as is broadly encompassed in the claims.
Regarding the “anti-NKp30 antibodies”: The 46 structures are identified by the specific CDR1/CDR2/CDR3 SEQ ID NO combinations outlined in the specification on p.21—27 for the 23 species “(1) through (23)”; on p. 33, Table 2 for 9 species having the CDR combination of species (10) but with specific variations/SEQ ID NOs in the non-CDR regions of the variable domain; and, on p.34—35, Table 3 for 14 species having post-translationally modified CDRs of species (23) and with specific variations/SEQ ID NOs with variations in the non-CDR regions of the variable domain. It is further noted that, in regards to the claim 9 limitation requirement that the antibody “bind NKp30 at a KD of 20.1 nM or less,” the disclosure supports that 45 of the 46 aforementioned anti-NKp30 single domain antibodies meet the limitation of instant claim 9 as “antibody #5” exhibits a KD that is greater than 20.1 nM (p.29, Table 1). Thus, for claims 3, 5-6, 10-12 and 15-22, the disclosure provides for 46 species of anti-NKp30 single domain antibodies or multifunctional fusion proteins comprising these 46 antibodies; and, for claim 9, the disclosure provides support for 45 species of anti-NKp30 single domain antibodies that bind NKp30 at a KD of 20.1 nM or less.
The state of the art around the time of the effective filing date of the claimed invention also does not disclose a representative number of species of the claimed antibodies or a structure function relationship that would allow a person of ordinary skill to predicably determine which antibodies would be able to perform the claimed functions.
Hummer, A.M., et al. Advances in computational structure-based antibody design Current Opinion in Structural Biology (2022), 74:102379, p.1-7, demonstrates ongoing unpredictability between antibody binding and epitopes. Specifically, Hummer teaches that traditional methods for antibody development, such as deriving antibodies from hybridomas of inoculated animals or from library assembly followed by display techniques are not only costly and time consuming but also are not necessarily able to produce antibodies that bind to the desired site (epitope) on an antigen. Hummer teaches that computational antibody design methods offer a way to overcome these limitations, but are held back by the lack of accurate antibody and antigen structures (p.1, col.2, para.2). Hummer provides a review on how advances in protein structure prediction and other areas are bringing us closer to being able to entirely computationally designed antibodies that bind strongly to a defined epitope (p.1, col.2, para.3) demonstrating that in 2022 predictable structure function relationships were still not known. Hummer acknowledges this in their discussion of future directions stating that “Several challenges still remain for true computational structure-based antibody design. While there has been great progress in protein structure prediction, current methods are not yet able to accurately predict the position of the side chain atoms or structural changes on binding. For antibodies, accurately modeling the CDR-H3 loop remains a major obstacle. Additionally, improvements in paratope and epitope prediction, both in terms of accuracy and specificity (predicting the types of binding interactions for residues), will be needed to help improve docking for high-throughput virtual screening.” (p.4, . col.2, para.3). Thus, Hummer teaches the difficulties in predicting the relationship between antibody structure and the epitopes to which they bind demonstrating a lack of predictability in the field between antibody structure and function.
In regards to claims to a product defined by function, without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 at1568 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genus. That is, the specification provides neither a representative number of antibodies that encompass the genus of antibodies as recited in the claims nor does it provide a description of structural features that are common to the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.
Overall, it is not evident from the disclosure or the prior art that applicant was in possession of an adequate number of antibodies that bind NKp30. There is no support providing that applicant had possession nor did applicant provided a sufficient description for all possible NKp30 single domain antibodies as instantly claimed. This subject matter was not described in the specification in such a way as to reasonably convey to one of ordinary skill in the art that applicant was in possession of the claimed invention at the time of filing and, therefore, the claims do not meet the written description requirement.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
Anti-NKp30 antibodies comprising the specific CDR1/CDR2/CDR3 sequences outlined for antibody species (1) – (26) in claim 4 are free of the prior art. Further, the specific VHH sequences recited by SEQ ID NOs: 1-23 and 117-139 of claims 7 and 8, which also define the CDR1, CDR2, and CDR3 regions for species supported by the disclosure, are also free of the prior art.
The closest prior art for the invention is provided by Loew, et al.—WO2020172605A1. Antibody molecules that bind to NKP30 and uses thereof (publication date: 08/27/2020; effective filing date: 02/21/2019; herein referred to as Loew). Loew teaches various anti-NKp30 antibodies including camelid antibodies (p.26, embodiment 97; p.80, 81, 83; p.140, #17) and multi-specific molecules thereof that also comprise cytokines (p.105-107; p.141, #25; p.26, #92). However, Loew does not teach antibodies that comprise the specific CDR1/CDR2/CDR3 SEQ ID NO combinations recited for the antibodies outlined in instant claim 4.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jami M Gurley whose telephone number is (571)272-0117. The examiner can normally be reached Monday - Friday, 8am - 4pm.
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647