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 .
Restriction/Election
Applicant’s election without traverse of Group I, drawn to a polypeptide comprising a heavy chain CDR3 (HCDR3) having an amino acid sequence set forth in SEQ ID NO: 4 and corresponding to claims 1-5, 7-11, 13, and 15 in the reply filed 08/28/2026 is acknowledged.
Applicant has further elected examination of the light chain species SEQ ID NO: 5, corresponding to SEQ ID NO: 6, AAS, and SEQ ID NO: 8.
Claim Status
Claims 1-5, 7-11, 13, 15, 18, 20-22, 24-25, and 27 are pending. Claims 18, 20-22, 24-25, 27 are withdrawn for being directed to a non-elected invention.
Claims 1-5, 7-11, 13, and 15 are under examination.
Claim Interpretation
Claim 1 recites a polypeptide comprising a heavy chain CDR3 having an amino acid sequence set forth in SEQ ID NO: 4. The specification does not provide a definition of a heavy chain CDR3 so the common definition in the art will be used. For example, Dondelinger (Front Immunol. 2018 Oct 16;9:2278) teaches: “In all cases, the variable domains of each [antibody] chain contain three hypervariable loops named complementary determining regions (CDR-1,-2, and-3). The CDRs are separated by structurally conserved regions called framework regions (FR-1,-2,-3, and-4) that form a “core” β-sheet structure displaying these loops on the surface of the variable domain.”(Pg. 2, Left column, Full Paragraph 2, Lines 15-20). As a “heavy chain CDR” exists in the context of a variable binding domain and claim 1 does not claim a binding function, claim 1 will be interpreted to include any polypeptide that comprises SEQ ID NO: 4. Accordingly, claims 2 and 3 are interpreted to encompass any polypeptide that comprises the three sequences SEQ ID NO: 2, 3, and 4.
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 5 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.
Regarding claims 5 and 13, the phrase "in particular" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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.
SCOPE OF ENABLEMENT
Claims 1-5, 7-11, 13, and 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a CD3-specific antibody and/or CD3-specific antibody binding region comprising a VH and VL with six CDRs, does not reasonably provide enablement for a polypeptide comprising a single HCDR3 set forth in SEQ ID NO: 4 or having 70% identity thereto. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims
Claims 1-5 are broadly directed to any polypeptide that comprises the sequence set forth in SEQ ID NO: 4 or having 70% identity thereto. Claim 1 does not recite a function Claims 2 and 3 are broadly directed to a polypeptide that comprises three CDRs, but does not claim any framework regions that are required to generate a functional heavy chain. Claim 4 provides a heavy chain variable region set forth in SEQ ID NO: 1, but permits mutations in the CDR regions. A single heavy chain set forth in SEQ ID NO: 1 is not sufficient to bind an antigen and therefore has no use. Claims 7-11, 13 claim a CD3 binding domain, however, none of the claims provide six CDRs in the context of VH and VL framework. While the specification provides embodiments that are enabled such as the generation of CD3 binding regions by pairing the heavy chain of SEQ ID NO: 1 with light chains known in the art, these features taught as critical in the specification must be recited in the claims for the claims to be enabled. (MPEP 2164.08(c)).
Nature of the Invention
The nature of the invention of claims 1-5 is a polypeptide comprising an HCDR3 having an amino acid sequence set forth in SEQ ID NO: 4 or having at least 70% sequence identity thereto. Claims 7-11 and 13 claim a binding moiety, but none of the claims provide six CDRs in the context of their respective heavy and light chain variable region framework which is required to enable the generation and use of a binding moiety. While the specification provides multiple embodiments of CD3 binding domains comprising heavy chain SEQ ID NO: 1 paired with light chains known in the art, these embodiments are not recited in the claims (Table 4, Pg. 33).
State of the Relevant Art & Level of Predictability in the Art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
The prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, the unpredictability of single amino acid changes in an antibody is underscored by Winkler (J Immunol. 2000 Oct 15;165(8):4505-14) who teaches that a single amino acid change in a CDR can result in unpredictable and substantial changes in antibody specificity; see entire document (e.g., the abstract).
Similarly, Herold et al. (Sci Rep. 2017 Sep 25;7(1):12276) performed single- and double-point mutations in exemplary antibodies and found that a single point mutation in the VH CDR region can completely abolish antigen binding (Page 8, Paragraph 1, Line 11).
Pertaining specifically to anti-CD3 binding regions, US2019/0352401A1 discloses an anti-CD3 antibody comprising an HCDR3 with more than 70% identity to the SEQ ID NO: 4. Importantly, each of the multispecific antibodies distilled to practice in US2019/0352401A1 comprised binding regions comprising three heavy chain CDRs and three light chain CDRs (see for example, Pg. 30-31, Table 6).
In all, the art shows that in order to enable the full scope of claim 1, the claim must provide all three heavy chain CDRs of the heavy chain and all three CDRs of the light chain(s) to which the heavy chain can bind and produce CD3 binding.
The amount of direction provided by the inventor and the existence of working examples
Table 4 of the specification shows the results of pairing various anti-CD3 antibody heavy chains with various light chains from known tumor antigen-associated monoclonal antibodies (Pg. 33). The specification teaches SEQ ID NO: 4 is the HCDR3 of the anti-CD3 clone SC5Ab1 (see Example 1). The SCAb1 heavy chain comprising HCDR1 SEQ ID NO: 2, HCDR2 SEQ ID NO: 3, and HCDR3 SEQ ID NO: 4 was able to retain CD3 binding when paired with many different light chains. Pertaining specifically to what is claimed, the specification does not provide any examples of a polypeptide comprising SEQ ID NO: 4 existing outside of the context a fully-defined antibody heavy chain. The specification also does not provide any examples of an isolated SC5Ab1 heavy chain with any kind of utility or binding ability. The specification does provide examples where the heavy chain SC5Ab1 is paired with either its native light chain or paired with various light chains of monoclonal antibodies known in the art. While not all heavy chain and light chain pairings were able to produce CD3 binding, it is noted that all examples distilled to practice required the pairing of three heavy chain CDRs with three light chain CDRs.
The quantity of experimentation needed to make or use the invention
The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and use the claimed polypeptide or CD3 binding regions without first making a substantial inventive contribution. Given that the nature of the invention is a polypeptide comprising single HCDR3, a person having ordinary skill in the art would have to perform extensive experimentation to use the polypeptide as claimed. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation.
In view of the lack of the predictability of the art to which the invention pertains, the lack of guidance and direction provided by applicant, and the absence of appropriate working examples in the disclosure and in the state of the art as a whole, undue experimentation would be required to use the claimed invention.
WRITTEN DESCRIPTION
Claims 7-11, 13, and 15 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention
The claims are directed to a polypeptide comprising a heavy chain CDR3 (HCDR3) having an amino acid sequence set forth in SEQ ID NO: 4. Claim 1, which is directed to the polypeptide only, does not claim explicitly or implicitly a binding function. In contrast, claim 7 claims a CD3 binding domain” comprising the polypeptide having the sequence set forth in SEQ ID NO: 4.
The instant specification teaches anti-CD3 antibody clone SC5Ab1, which comprises a heavy chain variable region SEQ ID NO: 1, comprising three heavy chain CDRs set forth in SEQ ID NOs: 2, 3, and 4 (Pg. 8, Lines 29-33). The specification does not disclose SEQ ID NO: 4 in the context of any other polypeptide other than a heavy chain variable region comprising a CDR1, a CDR2 and framework regions.
Pertaining to the claimed CD3 function, the specification demonstrates the heavy chain comprising CDRs SEQ ID NO: 2, 3, 4 can be paired with various light chains known in the art and retain the ability to bind CD3 (Pg. 33-34, Table 4). In these examples, the binding regions have 6 fully defined CDRs.
The state of the prior art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
The prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, the unpredictability of single amino acid changes in an antibody is underscored by Winkler (J Immunol. 2000 Oct 15;165(8):4505-14) who teaches that a single amino acid change in a CDR can result in unpredictable and substantial changes in antibody specificity; see entire document (e.g., the abstract).
Similarly, Herold et al. (Sci Rep. 2017 Sep 25;7(1):12276) performed single- and double-point mutations in exemplary antibodies and found that a single point mutation in the VH CDR region can completely abolish antigen binding (Page 8, Paragraph 1, Line 11).
In all, the art shows that fully defining an antibody binding region requires the identification of all 6 CDRs that define the binding regions of both heavy and light chain variable regions.
Claim analysis
In light of the teachings of the specification and the state of the relevant art, the claims have the following written description issues:
Claims 7 and 8 claim a CD3 binding domain while only providing the sequence of a single CDR – the HDCR3 set forth in SEQ ID NO: 4 or having 70% identity to SEQ ID NO: 4. As the claims have the function of binding CD3, all 6 CDRs need to be provided. Additionally, the CDRs cannot be claimed based on percent identity because even a single substitution, deletion or mutation can abolish binding specificity.
Claim 9 claims a group of antigen-binding proteins that bind human CD3, but only defines the sequence of the HCDR3 set forth in SEQ ID NO: 4 or having 70% identity to SEQ ID NO: 4. In order to claim the function of binding CD3, all 6 CDRs need to be provided. Additionally, the CDRs cannot be claimed based on percent identity because even a single substitution, deletion or mutation can abolish binding specificity.
Claims 10 and 11 provide the light chain variable regions of the CD3 binding domain, but the claims provide only 4 of the required 6 CDRs – 3 light chain CDRs and the HCDR3. Additionally, the CDRs cannot be claimed based on percent identity because even a single substitution, deletion or mutation can abolish binding specificity.
Claim 13 is directed to a binding moiety comprising the polypeptide of claim 1, but defines only the HDCR3 of the binding moiety.
Claim 15 is directed to a pharmaceutical composition comprising an effective amount of a polypeptide as claimed in claim 1, but as claim 1 does not sufficiently define a polypeptide with any binding function it is not possible to determine what an effective amount is.
Because these claims do not define all 6 CDRs of the heavy and light chain binding domains, one of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as is claimed. There is no disclosure of a correlation between structure and function that would allow those of skill in the art to recognize other members of the claimed genus from the disclosure.
That is, the specification provides neither a representative number of the encompassed antibodies, nor does it provide a descriptive of structural features that are common to the encompassed antibodies.
Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the artisan cannot envision the detailed structure of the encompassed antibodies and non-antibody proteins and therefore Applicant was not in possession of the instant claimed invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4-5, 7-9, 13, and 15 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by de Kruif (US2019/0352401A1, published 11/21/2019, effectively filed 03/30/2018).
The disclosure of de Kruif is directed to multivalent antibodies comprising binding domains that share common variable regions (see Abstract).
Regarding claim 1, pertaining to a polypeptide comprising a heavy chain CDR3 (HCDR3) having an amino acid sequence as set forth in SEQ ID NO: 4; or having at least 70% sequence identity thereto, de Kruif discloses the heavy chain SEQ ID NO: 145 of an anti-CD3 antibody (identified as clone MF9249), which comprises a region that encodes 12 out of 16 of the amino acids of instant SEQ ID NO: 4 (75%). The alignment is shown below:
Instant SEQ ID NO: 4 x de Kruif SEQ ID NO: 145 (aa 99-115)
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media_image1.png
80
196
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Greyscale
Regarding claim 4, wherein the polypeptide of claim 1 comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 1, or having at least 80%, or at least 85%, or at least 90%, or at least 95%, sequence identity thereto, de Kuif SEQ ID NO: 145 has 87.6% similarity to instant SEQ ID NO: 1. The alignment is shown below:
Instant SEQ ID NO: 1 x de Kruif SEQ ID NO: 145 (aa 99-115)
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media_image2.png
713
622
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Greyscale
Regarding claim 5, wherein the polypeptide according to claim 1 further comprises a CH1 region, in particular further comprising a CH1 region, a hinge, a CH2 region, and a CH3 region, de Kuif teaches a multivalent antibody structure comprising a VH-CH1-hinge-CH2-CH3 structure (Fig. 1a). The structure is provided below:
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media_image3.png
554
562
media_image3.png
Greyscale
Regarding claim 7, pertaining to a CD3 binding domain comprising the polypeptide according to claim 1, de Kuif discloses a CD3 antigen binding domain (clone MF9249) comprising the heavy chain variable region sequence SEQ ID NO: 145, which is 75% identical to instant SEQ ID NO: 4 as shown in claim 1 above.
Regarding claim 8, wherein the binding domain according to claim 7 further comprises a polypeptide comprising a light chain variable region, de Kuif discloses the anti-CD3 heavy chain variable region(clone MF9249) set forth in SEQ ID NO: 145 paired with a light chain ([0267], Lines 1-6)
Regarding claim 9, pertaining to a group of antigen-binding proteins that bind human CD3, wherein each antigen-binding protein within the group comprises a heavy chain variable region and light chain variable region, the heavy chain variable region comprising a HCDR3 having at least 70% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 4, de Kuif discloses a “super-cluster” which is a group of clones sharing the same VH V-gene and having at least 70% sequence identity in the HCDR3 ([0264], Lines 12-15). De Kuif discloses the CD3 binding domain of the “super-cluster” is from clone MF9249, with VH set forth in SEQ ID NO: 145.
Regarding claim 13, pertaining to a binding moiety comprising a polypeptide as claimed in claim 1, in particular wherein the binding moiety is a multispecific binding moiety, in particular a bispecific or trispecific antibody, de Kuif is directed to multivalent antibodies and provides for multivalent antibodies that include a CD3 binding region (see Fig. 14a, 14b).
Regarding claim 15, pertaining to a pharmaceutical composition comprising an effective amount of a polypeptide as claimed in claim 1, de Kuif discloses pharmaceutical compositions comprising an antibody of the invention and pharmaceutically acceptable carrier and/or diluent ([00368], Lines 1-3).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROL ANN CHASE whose telephone number is (571)270-0934. The examiner can normally be reached Monday-Friday 9:00am-6:00pm.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646
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