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
The election with traverse filed October 29, 2025, is acknowledged and have been entered. Applicant has elected Group I and a species of antibody of claim 12, wherein said isolated antigen binding protein is a humanized P8D10 VL-VH scFv antibody comprising an amino acid sequence set forth as SEQ ID NO: 112 or a functional fragment thereof. It is noted that the elected species is a humanized P8D10 VL-VH scFv antibody which does not comprise a human IgG constant region as recited in claims 4 and 5. It is further noted that the sequences in claim 1 are sequences of VH and VL from murine antibodies, so claim 12 which recites the humanized P8D10 VL-VH scFv antibody comprising an amino acid sequence set forth as SEQ ID NO: 112 or a functional fragment thereof is drawn to a humanized derivative antibody of claim 1 comprising a fragment of one or more of the sequences the sequences of claim 1.
Claims 1-20 are pending. Claims 4-11, 13-15 and 19-20 are withdrawn from further consideration by the examiner, under 37 CFR 1.142(b), as being drawn to a non-elected invention or non-elected species of election.
Claims 1-3, 12 and 16-18 are under examination.
Election/Restrictions
Applicant's traversal of the species requirement is acknowledged.
Applicant’s arguments have been carefully considered but have not been found persuasive for the following reasons:
In the response, Applicant traverses the requirement and argues that Applicant disagrees that there is a lack of unity since all claims either directly or indirectly depend on claim 1.
In response, this argument is not found persuasive because claim dependency is not disclosed as prima facie evidence that all claims share unity of invention and the different groups and species have been established to not share unity of invention (see MPEP § 1850 and 1893.03(d) for unity of invention analysis).
Therefore, the requirement is still deemed proper and is made FINAL.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
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 1-3, 12 and 16-18 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.
“[T]he 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 specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Regents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. 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. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The teachings of the specification and the claimed invention
The nature and scope of the claimed invention at issue in claims 1-3 and 16-18 is a genus of structurally and functionally diverse antigen binding proteins, or an immunologically active fragment or derivative thereof, which binds to an ETEC class 5 adhesin, wherein said isolated antigen binding protein comprises one or more variable regions or active fragment thereof of the sequences in claim 1. Claim 2 recites that the antigen binding protein can be a human antibody. Claim 12 then recites wherein said isolated antigen binding protein is a humanized P8D10 VL-VH scFv antibody comprising an amino acid sequence set forth as SEQ ID NO: 112 or a functional fragment thereof.
As a first point it is noted that the specification discloses that ETEC class 5 adhesins include 8 distinct adhesins as set forth in Table 1 copied below.
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474
607
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Accordingly, the claimed antigen binding proteins, or an immunologically active fragment or derivative thereof can broadly bind to one or more of these adhesins.
Secondly, claims 1-3 and 16-18 recite that they encompass derivatives thereof that only require one variable region or an active fragment thereof and the specification does not provide a limiting definition of the claimed “derivatives” or “active fragment thereof”. Notably, the specification says with respect to the term “derivative” that the definition “includes, but is not limited to” (see ¶ 76), and does not specifically limit the term “active fragment thereof” so these terms are not specifically limited by the specification.
In the antibody art, US 2014/0127209 A1 (Grabstein et al) discloses that derivatives of antibodies include those comprising at least one CDR with one or more amino acid additions, deletions or substitutions of a known CDR (see claim 21). Furthermore, US 2024/0067720 A1 (Liu et al) discloses that “As used herein, “antigen-binding fragment” includes a fragment of an antibody or a derivative thereof, typically including at least a fragment of the antigen-binding region or the variable region (e.g., one or more CDRs) of the parent antibody, and the fragment of the antibody or the derivative thereof retains at least some of the binding specificity of the parent antibody. Examples of the antigen-binding fragment include, but are not limited to, Fab, Fab′, F(ab′)2 and Fv fragments; diabodies; linear antibodies; single-stranded antibody molecules, such as sc-Fv; and nanobodies and multispecific antibodies formed from antibody fragments. When the binding activity of an antibody is expressed on a molar concentration basis, a binding fragment or a derivative thereof typically retains at least 10% of the antigen binding activity of the parent antibody. In one embodiment, the binding fragment or the derivative thereof retains at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the antigen binding affinity of the parent antibody. It is also contemplated that an antigen binding fragment of an antibody may include conservative or non-conservative amino acid substitutions that do not significantly change its biological activity (referred to as “conservative variants” or “functionally conservative variants” of the antibody).” (see ¶98). Accordingly, the claimed derivatives of claims 1-3 and 16-18 broadly, but reasonably include derivatives that retain at least some of the binding specificity of the parent antibody, including those that comprise fragments of the parent antibody and CDRs with one or more amino acid additions, deletions or substitutions. Then with respect to claim 12 the claimed “functional fragment thereof” is not defined by any fragment length, so these functional fragments may comprise any undefined part of a humanized P8D10 VL-VH scFv antibody comprising an amino acid sequence set forth as SEQ ID NO: 112.
The inventors disclose multiple murine antibodies that bind to class 5 adhesins (see pages 54-56) as set forth in Table 3 (see page 59) copied below.
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630
561
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64
592
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These antibodies and others are further characterized in Table 4 to identify partial epitope structure (see pages 61 and 62) copied below.
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1039
652
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From these disclosed antibodies, it is clear that the clones have different binding characteristics with some only binding to one antigen such as the elected P8D10 antibody which only binds to CfaE, while others cross-react with other adhesins and the antibodies bind multiple different conformational or liner epitopes. However, each of these antibodies comprise a heavy chain variable region comprising 3 CDRs and a light chain variable region comprising 3 CDRs that are responsible for the particular binding characteristics of each antibody (see Figures and Examples). Notably, the antibodies were created by mouse immunization and hybridoma generation (see pages 54-56). However, the specification does not provide evidence that antibodies with less than the 6 CDRs of the P8D10 antibody bind to CfaE, which CDRs can be altered to retain binding to CfaE or create binding to a different Class 5 adhesin or what other derivative antigen binding proteins would bind to one or more of the Class 5 adhesins.
State of the Art
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single antigen. For example, Lloyd et al (Protein Engineering, Design & Selection, 22:159-168, 2009) teach that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences and can bind different epitopes on the antigen (see, e.g., Discussion). Similarly, Edwards et al (J Mol Biol, 14;334(1):103-118, 2003), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein with 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (see Abstract).
It is also known in the antibody art that the formation of an intact antigen-binding site in a conventional 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) that provide the majority of the contact residues for the binding of the antibody to its target epitope. See Almagro et al, (Frontiers in Immunology (2018) 8: 1751, pages 1-19), (“The IgG Molecule” (page 3) and Figure 1). Sela-Culang (Frontiers in Immunology (2013) 4: 302, pages 1-13) further teaches, “A major focus in analyzing the structural basis for [antigen] recognition has been in identifying the exact boundaries of the CDRs in a given [antibody]. It is a common practice to identify paratopes through the identification of CDRs” (page 3, left column, “CDRs Identification”).
Although 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. Ni (The Protein Journal (2024) 43: 683-696) teaches, “Mutations, even one mutation, introduced in the CDRs through [somatic hypermutation] can change the binding properties and repertoire of antibodies. However, how just one-point mutation can dramatically change the recognition profiles of the antibody is still unclear” (Introduction). Furthermore, while affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody, those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori (Almagro, pages 3 and 6-7).
Therefore, it is expected that all 6 CDRs need to be grafted into antibody framework regions to retain the requisite specificity and functionality of the parent antibody. Notably, as antibodies are produced by genetic recombination and affinity maturation via mutations in the hypervariable CDR regions, the CDRs of one antibody with a particular function does not inform the skilled artisan as to other CDRs in antibodies that could be obtained with the same function, other derivatives comprising fragments as claimed that retain at least some of the binding specificity of the parent antibody or which fragments of a humanized P8D10 VL-VH scFv antibody comprising an amino acid sequence set forth as SEQ ID NO: 112 would bind to CfaE.
Claim Analysis
The nature and scope of the claimed invention is discussed above. In this case the specification does not disclose species representative of the claimed genera.
As an example to explain why the genera lack written description it is noted that merely binding an ETEC class 5 adhesin does not adequately describe such genera of antigen binding proteins, or an immunologically active fragment or derivative thereof, which binds to an ETEC class 5 adhesin, wherein said isolated antigen binding protein comprises one or more variable regions or active fragment thereof of the sequences in claim 1 or a functional fragment thereof of claim 12 because binding to one or more of eight different antigens does not describe the structure of a derivative or fragment that has this function. For example, disclosing the clone P8D10 antibody which binds to CfaE, is not representative of derivatives thereof that bind to CsbD or any other different adhesin. Additionally, disclosing the clone P8D10 antibody which binds to CfaE, is also not representative of derivatives thereof that bind to CfaE because one cannot predict which derivatives such as derivatives with altered CDR residues would retain binding to CfaE or which human monoclonal antibody derivatives of claim would bind to CfaE. Reciting an derivative or fragment that binds to an antigen is insufficient to describe the genus that binds to that antigen because the structure of one antibody that binds an antigen will vary widely from the structure of other antibodies that bind the antigen.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen as evidenced by Lloyd et al and Edwards et al above. For example, with respect to binding CfaE, the art of WO 2020/097627 (Klempner et al) discloses 3 different human antibodies that bind to CfaE which meet the scope of the derivatives of instant claims 1-3 and 16-18, and these antibodies are not disclosed in the instant specification.
Accordingly, one of skill in the art would not be able to immediately envision, recognize or predict the structure of the full scope of the derivatives encompassed by the claims and would not recognize that Applicant was in possession of the claimed invention.
Once again, the specification does not characterize species representative of the claimed genus as it does not characterize which CDR amino acids of the disclosed antibody are required to maintain binding. Furthermore, the specification does not disclose how to derivatize the P8D10 antibody to bind a different adhesin, so the specification is not in possession of derivative antibodies that bind a different adhesin than the parent antibody binds. Notably, the claims do not require all 6 CDRs of a parent antibody from both binding domains and as the specification does not fully characterize which CDR residues can be varied or which parts of can be replaced to retain binding function or alter binding function, the disclosed antibody species is not representative of the claimed genus. Accordingly, one of skill in the art would not be able to immediately envision, recognize or predict the structure of derivatives or fragments thereof comprising less than all 6 of the recited CDRs in the proper context of heavy and light chain frameworks which would have the function of binding to CfaE and would not recognize that Applicant was in possession of the claimed invention.
Given the lack of particularity with which the antibodies are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize or distinguish at least most of the members of the claimed genera, to which the claims are directed; and therefore the specification would not reasonably convey to the skilled artisan that Applicant had possession of the claimed invention at the time the application was filed.
In this case, it is suggested this rejection could be obviated by amending the claim 1 (along with appropriate corresponding amendments to the other claims) to recite:
An isolated antibody that binds to CfaE, wherein the antibody comprises a light chain variable region comprising the three light chain CDR sequences in SEQ ID NO:112 and a heavy chain variable region comprising the three heavy chain CDR sequences in SEQ ID NO:112.
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)(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 1-3, 12 and 16-18 are rejected under 35 U.S.C. 102(a)(1) 35 U.S.C. 102(a)(1) as being anticipated Klempner et al (WO 2020/097627 A1).
The scope of the claims is herein interpreted as follows:
Claim 1 recites an isolated antigen binding proteins, or an immunologically active fragment or derivative thereof, which binds to an ETEC class 5 adhesin, wherein said isolated antigen binding protein comprises an active fragment thereof of one of the sequences in claim 1. Claim 12 then recites wherein said isolated antigen binding protein is an scFv comprising a functional fragment of an amino acid sequence set forth as SEQ ID NO: 112. Notably, the claimed derivatives, active fragments and functional fragments are not defined in a limited manner in the specification.
In the antibody art, US 2014/0127209 A1 (Grabstein et al) discloses that derivatives of antibodies include those comprising at least one CDR with one or more amino acid additions, deletions or substitutions of a known CDR (see claim 21). Furthermore, US 2024/0067720 A1 (Liu et al) discloses that
“As used herein, “antigen-binding fragment” includes a fragment of an antibody or a derivative thereof, typically including at least a fragment of the antigen-binding region or the variable region (e.g., one or more CDRs) of the parent antibody, and the fragment of the antibody or the derivative thereof retains at least some of the binding specificity of the parent antibody.
Accordingly, the claimed antigen binding proteins comprising derivatives, active fragments and functional fragments as claimed are broadly, but reasonably determined to include any antigen binding proteins that bind to an ETEC class 5 adhesin, wherein the antigen binding polypeptide comprises at least a part of one CDR sequence of the sequences of claim 1 and an scFv comprising at least a part of one CDR sequence of claim 12.
Regarding claim 1, Klempner et al discloses isolated antigen binding protein that bind to the ETEC class 5 adhesin, CafeE, wherein the binding domain comprises the amino acid fragment “PRT” in LCDR3 (see SEQ ID NO:22 and page 2) and in the P8D10 antibody (see Figure 14(A), SED ID NO:37), the LCDR3 also comprises the amino acid fragment “PRT”. Regarding claims 3 and 12, Klempner et al discloses an scFv comprising the sequences of the invention (see page 4). Regarding claim 2, Klempner et al discloses that the antibody and be a human or humanized antibody (see page 22). Regarding claims 16-18, Klempner et al discloses pharmaceutical compositions comprising the antibodies of the invention and vaccine comprising the antibody of the invention (see pages 1, 4, 10, 27-28 and 44).
Therefore, the prior art is deemed to anticipate the instant claims absent a showing otherwise.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brad Duffy whose telephone number is (571) 272-9935. The examiner works a flexible schedule.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Julie Wu can be reached on (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
January 30, 2026