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 .
Election/Restrictions
Applicant’s election with traverse of Group I (claims 2-3, 6, 8, 39); and election of species without traverse: CDRs from clone 3C3-1 (i.e., CDR-H1 SEQ ID NO: 13; CDR-H2 SEQ ID NO: 18; CDR-H3 SEQ ID NO: 23; CDR-L1 SEQ ID NO: 28; CDR-L2 SEQ ID NO: 33; CDR-L3 SEQ ID NO: 38); and VH SEQ ID NO: 153 and VL SEQ ID NO: 154) in the reply filed on is acknowledged. The traversal is on the ground(s) that the Examiner has made a restriction between Groups I-VI. Applicants’ arguments have been considered but are non-persuasive because WO 2016/179319 Al discloses a nucleic acid molecule comprising a nucleotide sequence encoding a CAR wherein the CAR comprises a target binding domain, a hinge region, a transmembrane domain and an intracellular domain comprising a signal transduction domain (claim 1). The nucleic acid molecule further comprises a CD3 zeta signal transduction domain or a Fe receptor signal transduction domain ( claim 11 ). The target binding domain binds a target selected from a group that includes EphA3 ( claim 22). The target binding domain binds to a biomolecule that binds to cell surface marker on a target cell (claim 23), such as EphA3 (claim 25).
Additionally, WO 2019/099707 Al discloses a polypeptide comprising a CAR wherein the CAR comprises an amino acid modification in the hinge domain or transmembrane domain and/or intracellular domain, wherein the amino acid modification modulates the activity of a CAR-T cell ( claim 1 ). The transmembrane domain comprises an inserted polypeptide from a protein known to be multimeric or monomeric ( claim 5). The protein known to be multimeric comprises a receptor tyrosine kinase selected from a group of receptors that includes EphA3 ( claim 7).
Both prior art references mention binding Chimeric Antigen Receptors (CAR) binding to the target EphA3 (See for example paragraph 10 for WO 2016/179319 Al or paragraph 16 for WO 2019/099707 Al). The references also disclose competing and cross-competing target binding molecules ( See paragraph 53 of WO 2016/179319 Al and paragraph 88 of WO 2019/099707 Al). CART-Cell therapies in Glioblastoma is known in the art (See Migliorini et al (2017), abstract, Table 1). It is also known in the art that the inclusion of an endogenous CMV specific T cell receptor results in enhanced proliferation of CAR-T cells (See Maus et al. (2016), page 1877, left hand column). Additionally methods of preparing such bispecific T-cell populations and claims that define additional features that are known to be critical components of a CAR (such as a hinge, transmembrane domain, co-stimulatory domain or signaling domain) are old and well known in the art. Therefore, the product of Group V, lacks a special technical feature absent from the prior art as the references suggest a product as recited in Group V.
The test for propriety of restriction is not whether the inventions are related but rather whether they are distinct and whether it would impose a burden on the examiner to search and examine multiple inventions in a single invention. Groups I-VI are independent and distinct, each from the other, requiring separate searches, which would be unduly burdensome. Furthermore, separate search terms would be required for searching the literature, eg. a search of the literature for a method of treating cancer with an antibody to EphA3 would not necessarily reveal art for a T-cell that comprises (a) a T-cell receptor (TCR) that expresses a TCR that is specific for a CMV antigen; and (b) an antigen-binding molecule that binds to EphA3.
The Groups as delineated in the restriction requirement of 12/15/2025 are patentably distinct one from the other such that each invention could, by itself, in principle, support its own separate patent (as shown by the arguments put forth in the written restriction requirement).
The requirement is still deemed proper and is therefore made FINAL.
Claims 15-17, 20-21, 23, 25, 27, 42, 49, 51, 53, 54, 56 and 58, are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Previously presented claims 2-3, 6, 8, 39, and new claim 75, (2/13/2026), are under consideration by the Examiner.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 9/22/2022 is in compliance with the provisions of 37 CFR 1.97 and has been considered by the examiner.
Applicant is reminded of their duty to disclose to the Office all information known to the person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section”.
Claim Rejections - 35 USC § 112(a), first paragraph, enablement
4. 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.
4a. Claim 6 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The hybridoma cell lines recited in claim 6, deposit # 3C3-1, and 2D4-1, are essential to the claimed invention. The reproduction of antibodies from the disclosed hybridomas is an extremely unpredictable event. The hybridomas 3C3-1 and 2D4-1 must be obtainable by a repeatable method set forth in the specification or otherwise be readily available to the public. The instant specification does not disclose a repeatable process to obtain the hybridomas, and it is not apparent if the hybridomas are readily available to the public. If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the hybridomas have been deposited under the Budapest Treaty and that the hybridomas will be irrevocably and without restriction or condition be released to the public upon the issuance of a patent would satisfy the deposit requirement made herein. See 37 CFR 1.808. Further, the record must be clear that the deposits will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent whichever is longer. See 37 CFR 1.806. If the deposits have not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposits have been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
Amendment of the specification to disclose the date of deposits and the complete name and address of the depository is required.
If the deposits were made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate that the hybridomas described in the specification as filed is the same as that deposited in the depository. Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposits are identical to the biological material described in the specification and in the applicant's possession at the time the application was filed.
Applicant's attention is directed to In re Lundak, 773 F.2d. 1216, 227 USPQ 90 (CAFC 1985), and 37 CFR 1.801-1.809 for further information concerning deposit practice.
Claim Rejections - 35 USC § 112(a), first paragraph, written description
4b. Claims 2-3, 6, 8, 39, and 75, 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.
Independent claim 1 recites “an EphA3 binding agent comprising: (i) a heavy chain immunoglobulin variable region (VH) polypeptide comprising a CDR 1 having an amino acid sequence at least 70% identical to any one of SEQ ID NOs:13; a CDR 2 having an amino acid sequence at least 70% identical to any one of SEQ ID NOs: 18; and a CDR 3 having an amino acid sequence at least 70% identical to any one of SEQ ID NO: 23; and (ii) a light chain immunoglobulin variable region (VL) polypeptide comprising a CDR 1 having an amino acid sequence at least 70% identical to any one of SEQ ID NOs: 28; a CDR 2 having an amino acid sequence at least 70% identical to any one of SEQ ID NOs: 33; and a CDR 3 having an amino acid sequence at least 70% identical to any one of SEQ ID NOs:38.”
To support such a claim, the instant application discloses an EphA3 antibody comprising
HCDR1 /HCDR2/HCDR3/LCDR1 /LCDR2/LCDR3 sequence combination of SEQ ID NOs: 13/18/23/28/33/38.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, 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 genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3).
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), the following is noted.
To show invention, a patentee must convey in its disclosure that it “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002).
Further, recent court cases have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi. (Fed Cir, 2017-1480. 10/5/2017). Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it.
Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
In the instant case, the specification discloses an EphA3 antibody which comprises a heavy chain complementarity determining region (HCDR) sequences contained within the heavy chain (VH) polypeptide of SEQ ID NO: 153 and a light chain complementarity determining region (LCDR) sequences contained within a light chain (VL) polypeptide of SEQ ID NO: 154. However, no structure of variants of this antibody comprising amino acid sequences “at least 70% identical to SEQ ID NO:13 (HCDR1)”, “at least 70% identical to SEQ ID NO:18 (HCDR2)”, “at least 70% identical to SEQ ID NO:23 (HCDR3)”, “at least 70% identical to SEQ ID NO:28 (LCDR1)”, “at least 70% identical to SEQ ID NO:33 (LCDR2)”, “at least 70% identical to SEQ ID NO:38 (LCDR3)”, “at least 70% identical to SEQ ID NO:153 (VH)” and “at least 70% identical to SEQ ID NO:154 (VL)” have been described (see claim 2a (i)-(ii). As such, the structure required of an antibody such that it has all of the functions recited in the independent claim is not disclosed in the specification as filed. Applicant is reminded that the courts have long ruled that “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester. 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of an antibody does not provide evidence of possession of the antibody itself.
It is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR 1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the parent immunoglobulin (Janeway et al., 1997, see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., 1982, see entire document, particularly the abstract and the middle of the left column of page 1982). As discussed above, only an EphA3 antibody comprising a heavy chain complementarity determining region (HCDR) sequences contained within a heavy chain variable region (HCVR) of SEQ ID NO: 153 and a light chain complementarity determining region (LCDR) sequences contained within a light chain variable region (LCVR) of SEQ ID NO: 154, or an EphA3 antibody comprising a HCDR1 /HCDR2/HCDR3/LCDR1 /LCDR2/LCDR3 sequence combination of SEQ ID NOs: 13/18/23/28/33/38 has been described.
Indeed, in AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) the court ruled that all of the antibodies disclosed by AbbVie were all structurally similar as they were variants of a starting antibody named Joe9 and therefore did not serve to inform artisans as to the breadth of structures which had the recited function of cytokine binding. In the instant application, the instant claims recite antibodies to be used in the claimed methods while the specification does not disclose structures which necessarily have the requisite functions. The instant specification fails to disclose sufficient structural information to indicate to artisans that Applicant had possession of the “at least 70% identical” antibodies as presently claimed. Therefore, the broad genus of antibodies recited in Applicant’s claimed product lacks adequate written description because there does not appear to be sufficient correlation between the structure of the antibodies in question and their recited functional activities. As such a skilled artisan would reasonably conclude that Applicant was not in possession of the recited genus of antibodies claims and thus logically could not be in possession of such antibodies at the time the instant application was filed. Therefore, there is insufficient written description for the genus of antibodies having the claimed “limitations” at the time the invention was made and as disclosed in the specification as filed under the written description provision of 35 USC 112.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision. (See page 1115).
Applicant has claimed a broad genus of antibodies that are recited as binding EphA3. The instant claims appear to recite active mutagenesis of structural features yet data concerning mutagenesis either at the single amino acid level of CDR sequences does not appear to be present in the specification as filed.
Claim 3a (i) and (ii) claims an antibody wherein: a. (i) the VH polypeptide comprises an amino acid sequence set forth in SEQ ID NO:153 or an amino acid sequence at least 70% identical thereto; and/or (ii) the VL polypeptide comprises an amino acid sequence set forth in SEQ ID NO:154 or an amino acid sequence at least 70% identical thereto; thus can bind to EphA3 and thus it is not clear what the full extent of the genus of antibodies even encompasses. It should be noted that the epitope/sequence of the antigen is a fixed thing whereas claims which recite “70% identity” to sequence information, such as CDR sequences reasonably encompass variants. As set forth in Amgen v. Sanofi, knowing the structure of what is being bound does not provide knowledge of the structure of the antibody that is being claimed. It should also be noted that the USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. This Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies and states: “In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”. Thus, claims 60-62, and 67 lack adequate written description for the claimed antibody as they simply fail to recite what the antibody is (i.e. its sequence/structure).
Claim 2(a) recites various amounts of structure which must be present within the claimed antibodies by way of CDR sequences. The breadth of claim 2(a) requires only “70% identical” to SEQ ID NOs recited. Furthermore, claim 3a (i)-(ii) due to the recitation of “and/or” between limitations requires only a VH identified by SEQ ID number to be present. The breadth of this claim is expanded further by language which allows for one or more mutations as compared to the recited sequence, and could be from more than one antibody clone.
It is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1,2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope.
As has already been stated above, the instant specification does not provide any mutagenesis data concerning how disclosed CDR sequences can be mutated and maintain binding at the single amino acid level, by swapping CDR sequences, or by doing both simultaneously. Thus, there does not appear to be any reasonable disclosure of how the CDR sequences of the lead clones can be mutated and/or mixed and matched while maintain the function of antigen binding. Note that given that alterations as small as a single amino acid residue change can abrogate binding as set forth by Rudikoff et al., completely random CDR sequences which also can additionally comprise one or more point mutations within the paucity of specific structure which is required to be present does not reasonably appear to be correlated with maintenance of the function of antigen binding.
It should also be noted that data showing that for example an isolated peptide consisting of a single CDR sequence maintains binding to antigen has not been provided. Thus, artisans would reasonably expect that only antibodies which have six fully defined CDR sequences obtained from the same lead clone will maintain the recited function of antigen binding based upon the data presented in the instant specification.
Therefore, it appears that the broad genus of antibodies that bind EphA3 claimed by Applicant lacks adequate written description because there does not appear to be sufficient correlation between the structure of the claimed antibodies and the function of binding to EphA3. As such, a skilled artisan would reasonably conclude that Applicant was not in possession of the claimed genus of antibodies as well as pharmaceutical compositions comprising such antibodies at the time the instant application was filed.
Claim Rejections - 35 USC § 112(a), scope of enablement
4c. Claims 2-3, 6, 8, 39 and 75 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 an EphA3 antibody comprising a HCDR1 /HCDR2/HCDR3/LCDR1 /LCDR2/LCDR3 sequence combination of SEQ ID NOs: 13/18/23/28/33/38, does not reasonably provide enablement for an antibody as recited in claim 2. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Instant claim 2a encompasses EphA3 antibody variants with amino acid substitutions, insertions or deletions in the heavy chain CDRs, H1, H2 and H3 and amino acid substitutions, insertions or deletions in the light chain CDRs, L1, L2 and L3. Thus, these claims encompass variant antibodies, while the specification only discloses an antibody which comprises heavy chain complementarity determining region (HCDR) sequences contained within a heavy chain polypeptide (VH) of SEQ ID NO: 153 and a light chain complementarity determining region (LCDR) sequences contained within a light chain polypeptide (VL) of SEQ ID NO: 154. Thus, there is insufficient guidance and direction as to make and use all the encompassed antibodies that are encompassed by the scope of the claims. The genus encompasses variant antibodies that comprise disparate amino acid sequences, including numerous differences in linear and conformational epitopes. The specification does not provide sufficient guidance as to which of the amino acids of the heavy chain of SEQ ID NO:153 may be changed while structural or functional activity and specificity of the antibody is retained. For example, Lederman et al. disclose that a single amino acid substitution in a common allele ablates binding of a monoclonal antibody (see abstract). Li et al. also disclose that dissociation of immunoreactivity from other biological activities when constructing analogs (see entire document). Because of this lack of guidance, the extended experimentation that would be required to determine which modifications would be acceptable to retain occluding structural and functional activity, and the fact that the relationship between the sequence of a protein/peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable it would require an undue amount of experimentation for one of skill in the art to arrive at the claimed invention. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states on page 1404:
"Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. The nature of the invention is a method of using engineered antibodies and immunotherapy where the relative level of skill of those in the art is deemed to be high. In view of the lack of the predictability of the art to which the invention pertains as evidenced by the Lederman et al and Li et al references, the lack of guidance and direction provided by applicant, and the absence of working examples, undue experimentation would be required to make and use the claimed antibody with no reasonable expectation of success, commensurate in scope with the claimed invention.
Claim 2a is overly broad because it recites “…at least 70% identical” because no guidance is provided as to which of the myriad of antibodies encompassed by the claims will retain the characteristics of the desired antibody. On page 19, lines 17-26, of the specification, Applicants disclose:
“In this specification, "EphA3" refers to EphA3 from any species and includes EphA3 isoforms, fragments, variants (including mutants), or homologues from any species.
As used herein, a "fragment", "variant", or "homologue" of a protein may optionally
be characterised as having at least 60%, preferably one of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence of the reference protein (e.g., a reference isoform). In some embodiments, fragments, variants, isoforms, and homologues of a reference protein may be characterised by ability to perform a function performed by the reference protein.”
On page 19, lines 3034, and page 20, lines 1-5, the specification discloses:
“A "variant' generally refers to a protein having an amino acid sequence comprising
one or more amino acid substitutions, insertions, deletions or other modifications relative to the amino acid sequence of the reference protein, but retaining a considerable degree of sequence identity (e.g., at least 60%) to the amino acid sequence of the reference protein. An "isoform" generally refers to a variant of the reference protein expressed by the same species as the species of the reference protein. A "homologue" generally refers to a variant of the reference protein produced by a different species as compared to the species of the reference protein. Homologues include orthologues.”
However, no actual or prophetic examples on expected performance parameters of any of the possible variants of the claimed antibody molecule have been disclosed except for an antibody, which has a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO:153, and a light chain comprising the amino acid sequence as set forth in SEQ ID NO:154. Furthermore, it is known in the art that even single amino acid changes or differences in the amino acid sequence of a protein can have dramatic effects on the protein's function.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Proc. Natl. Acad. Sci. USA 1982 Vol 79 page 1979). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. It is unlikely that an antibody as defined by the claims which may contain less than the full complement of CDRs from the heavy and light chain variable regions of an EphA3 antibody in unspecified order have the required binding function. The specification provides no direction or guidance regarding how to produce antibodies as broadly defined by the claims. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone.
As evidenced by Adair et al. (US Patent 6,632,927) transfer of CDR regions alone are often not sufficient to provide satisfactory binding activity in the CDR-grafted product (col.2 lines 58-61). Panka et al (Proc. Natl. Acad. Sci. USA Vol 85, 3080-3084, 5/88) demonstrate that a single amino acid substitution of serine for alanine results in decreased affinity. In at least one case it is well known that an amino acid residue in the framework region is involved in antigen binding (Amit et al, Science Vol 233, 747-753, 1986). One of skill in the art would neither expect nor predict the appropriate functioning of the antibody as broadly as is claimed. It is suggested that the specific CDR regions of both the heavy and light chain be explicitly recited within the claim. Therefore, in view of the lack of guidance in the specification and in view of the discussion above one of skill in the art would be required to perform undue experimentation in order to make and use the claimed invention.
Applicant has claimed a genus of antibodies which are required to have specific CDR sequences recited by SEQ ID NO. The only reasonable way to make an antibody that is guaranteed to have a specific sequence or sequences are required by the instant claims is to use the techniques or recombinant molecular biology. It is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR 1,2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway et al., see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., see entire document, particularly the abstract and the middle of the left column of page 1982).
As stated above the antibody sequences which are not fixed by the instant claim language can be effectively random and thus there does not appear to be any predictability as to which sequences will or will not maintain antigen binding activity except for those which have six fully defined non-degenerate CDR sequences, three in the VH and three in the VL. Thus, there is no disclosed data which would reasonably allow artisans to make the full breadth of what is encompassed by the instant claim language.
Therefore, in view of the breadth of the instant claimed invention, the guidance and direction of the instant specification and the teachings of the art, artisans would be unable to make and use the full breadth of applicant’s genus of EphA3 antibodies as presently claimed without first performing extensive unpredictable basic since research and experimentation.
Claim rejections-35 USC § 112, second paragraph
5. 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.
5a. Claims 2-3, 6, 8, 39, and 75 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 pre-AIA the applicant regards as the invention.
Claim 2, line 1, is vague and indefinite because it recites “an EphA3 binding agent” rather than the proper “an EphA3 antibody”. It is suggested that the phrase “an EphA3 binding agent” be deleted from the claim and substituted with “an EphA3 antibody” to obviate this rejection.
Similarly claims 3, 6, 8, 39, and 75 are rejected as vague and indefinite because they recite “an EphA3 binding agent” rather than the proper “an EphA3 antibody”
Claim 3, line 3, is vague and indefinite because it recites “and/or” which is confusing. It is suggested that the term “or” be deleted from the claim to obviate this rejection.
Claim 6 is indefinite in the recitation of “3C3-1” and “2D4-1” because its characteristics are not known. The use of "3C3-1” and “2D4-1" monoclonal antibodies as the sole means of identifying the claimed antibodies and hybridomas renders the claim indefinite because "3C3-1” and “2D4-1" are merely laboratory designations which does not clearly define the claimed products, since different laboratories may use the same laboratory designations to define completely distinct hybridomas or cell lines.
Conclusion
No claim is allowable.
Claims 2-3, 6, 8, 39, and 75 are rejected.
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/PREMA M MERTZ/ Primary Examiner, Art Unit 1646
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