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
Status of the Claims
1. Claims 1-25 are the original claims filed on 2/23/2023. In the Preliminary Amendment of 2/23/2023, claims 1, 5-7, 9-12, 14-16, 18, 20-21 and 23 are amended and claims 19, 22 and 24-25 are canceled. In the Response of 1/8/2026, Claims 1-7, 9-17, 21 and 23 are amended and new claims 26-30 are added.
Claims 1-18, 20-21, 23 and 26-30 are the pending claims.
The amendment of the claims raises new grounds for objection and rejection. The Office Action is final.
Priority
2. USAN 18/042,762, filed 02/23/2023, is a National Stage entry of PCT/CN2021/ 114088, International Filing Date: 08/23/2021, claims foreign priority to CN PCT/CN2020/110841, filed 08/24/2020, and claims foreign priority to CN PCT/CN2020/141398, filed 12/30/2020.
Information Disclosure Statement
3. As of 3/11/2026, a total of five (5) IDS are filed: 2/23/2023; 1/29/2024; 10/14/2024; 3/17/2025; and 9/16/2025. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Objections
Drawings
4. The objection to the drawing sheet for Figure 10B because it contains illegible foreign language text, i.e.,
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is withdrawn. The corrected drawing sheet is considered and entered.
Specification
5. The objection to the abstract of the disclosure because it contains the indefinite phrase “such as” is withdrawn. The amended abstract replaces “such as” with “including.”
6. The objection to the disclosure because of informalities is withdrawn. Both clean substitute and marked-up copies of the specification are included.
a) The specification is amended to rectify the improper use of the term, i.e., UniProt, Tween, GraphPad, CytoFlex, Cytotox, TSKgel, BiTE, which is a trade name or a mark used in commerce.
b) The specification is amended to delete the underline from the underlined text.
Claim Objections
7. The objection to Claims 1-18, 20-21 and 23 because of informalities is withdrawn.
a) Claim 1 is amended to recite “An isolated antibody or antigen-binding fragment thereof that specifically binds to ROR1, comprising complementarity-determining regions (CDR) CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3, wherein…”
b) Claims 1-18, 20-21 and 23 are amended to recite “antigen-binding fragment thereof” for consistency.
c) Claim 3 is amended to rectify the lack of clarity by the use of “is”/ “or” language
d) Claim 5 is amended to delete element (iii).
e) Claim 5(ii) is amended to recite “(ii) the antibody binds to the C-terminus of a human ROR1 Ig-like domain,”
f) Claims 12 and 13 are amended to delete “a set of six CDRs.”
g) Claim 21 is amended to clarify the language without a change in scope.
h) Claim 23 is amended to clarify the disorder associated with ROR1.
Rejections Withdrawn-in-part/ Maintained-in-part
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.
Written Description
8. The rejection of Claims 5(iii) and 23 and new claims 26-27 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 is withdrawn-in part (claim 5) and maintained-in part (claim 23).
withdrawn-in part (claim 5): claim 5 is amended to delete element (iii).
maintained-in part (claim 23 and new claims 26-27) claim 23 is amended to delete “detrimental” and to identify the ROR1 associated hematological malignancy or solid tumor. Inasmuch as claim 23 is drawn to an anti-ROR1 x anti-CD3 antibody, none of the claims from which it depends, namely, claims 12 and 27 define the structure for the “second antigen-binding site that specifically binds CD3.” The experimental data in Examples 7-9 demonstrate an anti-ROR1 x anti-CD3 antibody that is not correlated by a structure in the rejected claims.
It is noted that the features upon which applicant relies (i.e., the protein structure for the anti-ROR1 x anti-CD3 antibody from Examples 7-9) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The interpretation encompasses a genus of anti-ROR1 x anti-CD3 constructs that are not defined by the second binding site for CD3. Because applicant seeks patent protection for all such constructs, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Status of the Art for Antibodies
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody was still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has not provided a common structure sufficient to visualize the genus of all possible functional constructs but for the protein structure for the anti-ROR1 x anti-CD3 antibody from Examples 7-9. One of ordinary skill in the art would NOT have understood what clones functioned similarly, nor which VH and/or VL domains could be paired to the extent the construct performed in a predictable manner.
Therapeutic antibodies such as those instantly claimed are still not understood well enough to allow researchers to predict with certainty what modifications can be made to a primary antibody sequence such that binding is maintained. “[T]he major test of understanding is whether the changes associated with antibody maturation can be predicted with any reasonable accuracy, and whether there is sufficient information for developing therapeutic antibodies,” Vajda et al., “Progress toward improved understanding of antibody maturation,” Current Opinion in Structural Biology, 67 pp. 226-231 (2021 (PTO 892)) at p. 226, col. 2, lines 20-24.
As recently as 2020, researches were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34, 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the genus for reliably assigning different antibody structures based on sequence data for one bispecific anti-ROR1 x anti-CD3 antibody clone, which would support the premise that the inventors possessed the full scope of the claimed method of treatment invention.
The rejection of claims 23 and 26-27 is maintained.
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
9. The rejection of Claims 5 and 14 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
a) Claims 5 and 14 are amended to delete “for example” and “e.g.,” including the entire phrase.
b) Claims 5 and 14 are amended to delete the parenthetical text in its entirety.
New Grounds for Objection
Claim Objections
10. Claims 1-18, 20-21, 23 and 26-30 are objected to because of the following informalities:
a) Claims 1-2, 4-11 and 21 are objected to failing to identify the numbering system for the antibody amino acid residues for the CDRH1-3 and CDRL1-3 in claim 1. Re-instatement of the phrase “wherein the CDRs are defined according to Kabat numbering” could overcome the objection.
b) Amend claim 3 at line 7 to replace “;” with “,”.
c) Amend claim 5 to replace “11 %” with “11%”.
d) Amend claim 5 to replace the provisional limitation “can be reflected by” with a positive limitation such as “is measured by” or “is determined by.”
e) Amend claim 5 to replace “same-period” with “same period.”
f) Amend Claim 12 to correct improper punctuation: replace the comma between the CDR elements with a semi-colon. See Claim 13.
g) Claim 12 is improperly amended and does not demonstrate replacement of a comma with a period after “Kabat numbering.”
h) Claim 15 is improperly amended and does not demonstrate insertion of the term “the” after [[an]].”
i) Claim 17 is improperly amended and does not demonstrate insertion of the term “the” after [[an]].”
j) Claim 23 is objected to for depending from claim 27. It is improper for a claim to depend from a later claim. 37 CFR 1.75 (c) states: (c) One or more claims may be presented in dependent form, referring back to and further limiting another claim or claims in the same application. Dependent claims must refer back to an earlier claim.
k) Claims 14-18, 20, and 27-30 are objected to for depending from an objected claim, Claim 12.
Appropriate correction is required.
New Grounds for Rejection
Claim Rejections - 35 USC § 112
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.
11. Claims 5(iii) and 13 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) Claim 5(iii) is amended to recite “the antibody competes with an antibody with a VH/VL sequence pair of SEQ ID NOs: 42 and 43 for binding to ROR1.”
While one may be able to assay whether an antibody “competes” with the recited monoclonal antibody, it is apparent that the degree to which an antibody competes with another antibody is a relative or subjective expression, and the requisite degree to which the claimed antibody competes with a monoclonal antibodies cannot be ascertained from the disclosure.
Contrary to the assertion in the specification that such a binding assay determines whether two antibodies bind to the same antigenic determinant (i.e., epitope), competing antibodies do not necessarily bind the same epitopes. For example, “competing” antibodies may bind spatially overlapping but discrete epitopes. Simply because two antibodies cannot simultaneously occupy the same space, such an antibody, once bound to the antigen, sterically hinders or blocks binding of another such antibody. As another example, a “competing” antibody might not necessarily bind to the same epitope of an antigen as another antibody, if one of the antibodies induces conformational shifts in the three-dimensional structure of the antigen upon binding, which prevents binding of the other antibody to the antigen because the epitope to which it would otherwise bind is unrecognizable as a consequence of the structural change.
In addition, it is recognized that the degree of binding of an antibody, which is observed in the exemplified competitive binding assay, will depend upon the concentration of the detectably labeled antibody and the unlabeled competing antibody. Typically, the higher the concentration of the unlabeled competitor, the lower the percentage of binding of the labeled antibody. So, at high concentrations, any antibody might be deemed capable of “competing” for binding to an antigen with any other antibody, regardless of whether or not the different antibodies bind to the same, or even overlapping epitopes.
George et al. (Circulation. 1998; 97: 900-906), for example, describes different antibodies, which do not bind to the same epitope of an antigen, but are nevertheless capable of competing with one another for binding to the antigen; see entire document (e.g., page 903, paragraph bridging columns 1 and 2). More particularly, George et al. describes three antibodies, which bind decidedly different, non-cross-reactive epitopes on b2GPI; yet, George et al. teaches each is able to “compete” by a measurable extent with any of the others for binding to the antigen (page 903, paragraph bridging columns 1 and 2). For example, George et al. teaches monoclonal antibody ILA-4 competed with itself for binding to the antigen (% inhibition = 90 ± 11%), but George et al. discloses, despite its binding a non-overlapping epitope, monoclonal antibody ILA-1 also “competed”, albeit with monoclonal antibody ILA-4 for binding to the antigen (% inhibition = 9 ± 4%).
Accordingly, George et al. illustrates the capricious and arbitrary nature of determinations that different antibodies bind to the same or different epitopes, which are based upon the results of competitive binding assays, such as the assay exemplified in the specification
b) Claim 13 recites “are defined according to Kabat numbering,.” The claim contains a comma after numbering and before the period. The POSA cannot reasonably ascertain whether subject matter text is missing or the “,.” is a typographical error.
Conclusion
12. No claims are allowed.
13. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643