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 .
Claims Status
The amendments and remarks filed 07/14/2026 are acknowledged.
Claims 16-18, 20, 23, 26-27, 29, 36-37 and 54 are pending.
Claims 16, 23, and 36-37 are amended.
Claims 1-15, 19, 21-22, 24-25, 28, 30-35, and 38-53 are canceled. The Examiner notes that claims 44-52, which were directed to non-elected Group II, were canceled.
Claim 54 is new.
Applicant’s election without traverse of Group I, claims 16-18, 20, 23, 26-27, 29, 36-37, in the reply filed on 07/14/2026 is acknowledged. Applicant’s election of the following species in the reply filed 07/14/2026 are acknowledged: SEQ ID NO: 52 and PD-L1. During a telephone conversation with Attorney of Record Paul Calvo on 08/18/2026 a provisional election was made without traverse to prosecute the species of SEQ ID NO: 20 for the PD-L1 binding domain. Affirmation of this election must be made by applicant in replying to this Office action.
Therefore, claims 16-18, 20, 23, 26-27, 29, 36-37 and 54 are under examination.
Priority
The instant application is a 371 of PCT/NL2022/050174 and claims priority to Kingdom of the Netherlands Application NL2027891. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Priority is given with the earliest effective filing date of 03/31/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/24/2024 and 07/14/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Drawings
The drawings are objected to because:
(1) Figures 1A, 1B, 2, 5F, 7A, 7B, 7C, and 8 comprise multiple panels. 37 CFR
1.84(u) states that the different views must be numbered in consecutive Arabic numerals and that "partial views intended to form one complete view, on one or several
sheets, must be identified by the same number followed by a capital letter". Each panel
should be separately numbered.
(2) Figures 1A, 1B, 2, 3A1, 3A2, 3B1, 3B2, 5A, 5B, 5C, 5D, 5E, 5F, 6A3, and 6A4 have pixelated backgrounds in the graphs. 37 CFR 1.84(a)(1) which requires that “india ink, or its equivalent that secures solid black lines, must be used for drawings”.
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.
Claim Objections
Claims 16, 18, and 23 are objected to because of the following informalities: The claims recite an acronym (i.e. LAG-3, PD-L1, CDR, CH1, CL, CD80). The first time an acronym is used, it must be accompanied by the definition of the abbreviation. Appropriate correction is required.
Improper Markush Grouping
Claims 16, 17, and 26 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 within each of the options for the heavy chain variable region of the LAG-3 binding domain and for the heavy chain variable region of the PD-L1 binding domain are 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: the alternatives do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
For example, SEQ ID NOs: 52 and 53 as set forth as options a) and b) in claim 16 have 46.9% sequence identity. The HCDRs 1-3 of SEQ ID NO: 52 of the LAG-3 binding domain, disclosed as SEQ ID NOs: 70, 71, and 118, respectively, and the HCDRs 1-3 of SEQ ID NO: 53, disclosed as SEQ ID NOs: 64, 65, and 199, respectively [see page 40 of the instant specification], have 20%, 31%, and 24% sequence identity, respectively. This also applies to the options listed for the sequences of the HCDRs 1-3 of the PD-L1 binding domain. For examples, the HCDRs 1-3 of SEQ ID NO: 20, disclosed as SEQ ID NOs: 107, 108, and 109, respectively, and the HCDRs 1-3 of SEQ ID NO: 22, disclosed as SEQ ID NOs: 113, 114, and 115, respectively [see page 52 of the instant specification], have 66.7%, 82.5%, and 11.9% sequence identity, respectively. Therefore, the alternatives listed for HCDRs 1-3 do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
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.
Note: SEQ ID NOs: 70, 71, and 118 for the HCDRs 1-3, respectively, of SEQ ID NO: 52 for the LAG-3 binding domain, which are disclosed as the sequences of the HCDRs 1-3 in SEQ ID NO: 52 [see page 40 of the instant specification] and SEQ ID NOs: 107, 108, and 109 for the HCDRs 1-3, respectively, of SEQ ID NO: 20 for the PD-L1 binding domain, which are disclosed as the sequences of the HCDRs 1-3 in SEQ ID NO: 20 were found to be novel and non-obvious. The Examiner did not search additional species because the non-elected species do not fall within a proper Markush group. See MPEP 803.02(III)(C)(2).
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 16-18, 20, 23, 26-27, 29, 36-37 and 54 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 16 recites the limitations “wherein the LAG-3 binding domain comprises a heavy chain variable region comprising a) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3), of a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 52, and wherein the PD-L1 binding domain comprises a heavy chain variable region comprising: a) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3), of a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 20.”
It is well known to those skilled in the art that antibodies utilize various numbering schemes to facilitate comparison and analysis of their variable regions. The most commonly used schemes include Kabat, Chothia, and IMGT. These schemes differ in their approach to defining regions, particularly the hypervariable regions (CDRs) that are crucial for antigen binding. Specifically, these different CDR identification methods may often identify radically different stretches as CDRs, indicating that CDRs are not well defined (Sela-Culang et al., 2013; instant PTO-892; see Conclusion). For example, Sela-Culang shows in Table 3 below, a comparison of CDR regions using different numbering methods demonstrating the significant difference between the amino acid sequences depending on what numbering scheme is utilized.
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730
680
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Greyscale
The instant specification fails to clarify the issue, disclosing that the CDRs may be defined by different methods, including but not limited to, the Kabat numbering scheme, the Chothia numbering scheme, the numbering system of Honegger and Pluckthun, the numbering system of MacCallum, the numbering system of Lefranc, the numbering scheme of Honegger and Pluckthun, or according to IMGT [see page 8, lines 12-28 of the instant specification].
Therefore, without the amino acid sequences of each CDR defined by SEQ ID NO or numbering scheme, one of ordinary skill in the art would not know the boundaries of the CDR regions set forth in the recited VH SEQ ID NOs: 52 and 20. Thus, the scope of this claim is indefinite.
Claims 17-18, 20, 23, 26-27, 29, 36-37 and 54, which depend from claim 1, are therefore indefinite for the same reasons set forth above.
Note: For examination purposes, the Examiner will search SEQ ID NOs: 70, 71, and 118 for the HCDRs 1-3, respectively, of SEQ ID NO: 52 for the LAG-3 binding domain, which are disclosed as the sequences of the HCDRs 1-3 in SEQ ID NO: 52 [see page 40 of the instant specification] and SEQ ID NOs: 107, 108, and 109 for the HCDRs 1-3, respectively, of SEQ ID NO: 20 for the PD-L1 binding domain, which are disclosed as the sequences of the HCDRs 1-3 in SEQ ID NO: 20 [see page 52 of the instant specification].
Claims 18, 23, 27, and 36 recite the limitation “in particular”. It is unclear if what succeeds the “in particular” are required claim limitations or not. MPEP 2173.05(d) states, “Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim.” Therefore, the scope of these claims is indefinite.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), 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.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], 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 20 and 29 are rejected under 35 U.S.C. 112(d) or pre-AIA 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 20 recites the limitation “the multispecific antibody or variant thereof according to claim 16, wherein the antibody or variant is monovalent for binding to LAG-3” and claim 29 recites the limitation “the multispecific antibody or variant thereof according to claim 16, wherein the antibody or variant is monovalent for binding to PD-L1.” A monovalent antibody is a one-armed antibody that binds to only one antigen-binding site [see page 6 of Yoon, 2002; instant PTO-892]. Therefore, the multispecific antibody cannot be a monovalent antibody, and thus, claims 20 and 29 do not further limit claim 16. 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(a)
Written Description
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 16-18, 20, 23, 26-27, 29, 36-37 and 54 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.
Claim 16 is drawn to a multispecific antibody, or variant thereof that maintains the binding specificity of the antibody, wherein the antibody or variant thereof comprises a binding domain that specifically binds to an extracellular domain of LAG-3 and a binding domain that specifically binds to an extracellular domain of PD-L1, wherein the LAG-3 binding domain comprises a heavy chain variable region comprising a) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3), of a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 52, wherein the PD-L1 binding domain comprises a heavy chain variable region comprising: a) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3), of a heavy chain variable region having an amino acid sequence as set forth in SEO ID NO: 20; wherein each of the HCDRs may comprise at most three, two, or one amino acid substitution.
The specification teaches a LAG-3/PD-L1 bispecific antibody comprising a LAG-3 binding domain that comprises HCDRs 1-3 of SEQ ID NO: 52 and a PD-L1 binding domain that comprises HCDRs 1-3 of SEQ ID NO: 20, and wherein each binding domain comprises light chain CDRs 1-3 of SEQ ID NOs: 31, 32, and 33, respectively [see page 64, lines 4-10; page 72, lines 1-6; page 74, lines 8-12; page 76, lines 14-18; page 103, Table 10 of the instant specification]. However, the specification does not teach a functional multispecific antibody containing anything less than 6 CDRs for each of the binding domains and does not teach a functional antibody containing anything less than 100% sequence identity to the HCDRs 1-3 and LCDRs 1-3 of each of SEQ ID NOs: 52 and 20.
One means of providing adequate written description and evidence of possession of a claimed genus is through providing sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the genus is defined entirely by a desired function: specifically binds to an extracellular domain of LAG-3 and specifically binds to an extracellular domain of PD-L1. The claim requires only three CDRs for each of the binding domains (i.e. only requires the HCDRs 1-3) and allows for up to three amino acid substitutions within each of the HCDRs 1-3 for each of the binding domains. One of skill in the art could not envisage such a structure that would bind the target epitope with anything less than 6 CDRs for each of the binding domains.
In this case, claim 16 is drawn to a variable number of CDRs, e.g. only the HCDRs 1-3 for each of the binding domains, and to a variable sequence for each of the HCDRS 1-3. The art recognizes that a complete set of six CDRs comprise the binding region of an antibody (see Sela-Culang et al., 2013; instant PTO-892), and that even a single amino acid change to these regions can completely abrogate the binding specificity of an antibody (see Kussie et al., 1994; instant PTO-892). Thus, making changes to the CDR sequence of an antibody is a highly unpredictable process and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held
that:
...To fulfill the written description requirement, a patent specification must
describe an invention and does so in sufficient detail that one skilled in the art can
clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re
Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the
inventor] invented what is claimed."). Thus, an applicant complies with the written
description requirement "by describing the invention, with all its claimed limitations, not
that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention."
Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
A "representative number of species" means that the species, which are
adequately described, are representative of the entire genus. Thus, when there is
substantial variation within the genus, one must describe a sufficient variety of species
to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if
the disclosure "indicates that the patentee has invented species sufficient to constitute
the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v.
Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir.
2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus
after only describing a limited number of species because there may be unpredictability
in the results obtained from species other than those specifically enumerated."). "A
patentee will not be deemed to have invented species sufficient to constitute the genus
by virtue of having disclosed a single species when ... the evidence indicates ordinary
artisans could not predict the operability in the invention of any species other than the
one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir.
2004).
Thus, based on the teachings of the instant specification and the art, applicant has failed to meet the written description of a multispecific antibody comprising a binding domain that specifically binds to an extracellular domain of LAG-3 and a binding domain that specifically binds to an extracellular domain of PD-L1 that comprise less than the full set of six CDRs for each of the binding domains. Therefore, one of skill in the art would not conclude that Applicant was in possession of the antibodies that are able to bind LAG-3 and PD-L1 that comprise less than the full set of six CDRs for each of the binding domains.
Claims 17-18, 20, 23, 26-27, 29, 36-37 and 54, which depend from claim 16, are therefore rejected for the same reasons set forth above.
Allowable Subject Matter
The sequences of SEQ ID NOs: 70, 71, and 118 for the HCDRs 1-3, respectively, of SEQ ID NO: 52 for the LAG-3 binding domain, which are disclosed as the sequences of the HCDRs 1-3 in SEQ ID NO: 52 [see page 40 of the instant specification] and SEQ ID NOs: 107, 108, and 109 for the HCDRs 1-3, respectively, of SEQ ID NO: 20 for the PD-L1 binding domain, which are disclosed as the sequences of the HCDRs 1-3 in SEQ ID NO: 20, are free of the prior art.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571) 272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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