DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The listing of claims filed on 6/8/26 has been entered; no amendments are indicated. Claims 1-30 are pending.
Applicants’ election of an antibody comprising a heavy/light chain sequence pair of SEQ ID NO: 20/45 as the species of antibody in the reply filed on 6/8/26 is acknowledged. Applicants indicate the elected species reads on claims 1-30.
Claims 1-30 are under consideration.
Specification
The disclosure is objected to because of the following informalities:
---The table on page 64 of the specification is illegible due to a small font and blurriness. Per MPEP 608.01.I, “papers that are to become a part of the permanent [USPTO] records in the file of a patent application or a reexamination proceeding, in a form that is clear and reproducible. If the papers are not of the required quality, substitute papers of suitable quality will be required”. See also 37 CFR 1.52(a). As such, Applicants must correct the specification such that the table on page 64 is legible.
---In each of ¶ 25 (page 3), ¶ 76 (page 6), Item 38 on page 21, and Item 108 on page 26, “Fab2” should be “F(ab’)2”.
---The specification refers to “SEQ ID Nos 51-200” at ¶ 14, and “SEQ ID Nos: 151-175” at ¶ 60. In the most recent sequence listing (filed on 2/22/24), each of these sequences is blank; i.e., only contains a “000” entry. These sequence identifiers should be removed from the specification as there is no amino acid sequence associated with them. If the sequences are blank because they are three amino acids in length or shorter, the references to the sequence identifiers in the specification should be replaced with the actual amino acid sequences.
Appropriate correction is required.
Drawings
Corrected drawings in compliance with 37 CFR 1.121(d) are required because:
---Figure 9A includes 6 amino acid sequences having more than three consecutive amino acids, but does not identify these sequences by reference to the appropriate sequence identifier either in the figure itself or in the brief description of the figure in the specification, as required by the rules for sequences (37 CFR 1.821(d)). If each sequence is already included in the sequence listing, either as an entire sequence or portion thereof, the objection can be overcome by adding the appropriate sequence identifier, or residues of the appropriate sequence identifier, to the figure itself or the brief description of figure in the specification. Otherwise, the sequence listing must first be updated to include the sequence, and then the sequence identifier must be added.
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). Applicants are advised to employ the services of a competent patent draftsperson outside the Office, as the USPTO no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Claim Objections
Claim 1-30 are objected to for the following informalities:
In clam 1, the abbreviation “IgE” should be accompanied by the full terminology the first time it is used in a series of claims; e.g., “immunoglobulin E (IgE)”. See the specification at ¶ 1 (page 1).
In claim 8, line 2, “β5-helix region” is missing an article; i.e., “a β5-helix region”.
In claims 8, 14 and 15, the abbreviations “β5” (claim 8), “β3” (claim 14) and “β4” (claim 15) should be accompanied by the full terminology the first time each is used in a series of claims; e.g., “fifth β-sheet (β5)”; “third β-sheet (β3)”; and “fourth β-sheet (β4)”. See the Brief Description of Figure 8.
In claim 8, line 3, “helix”, “β5-helix region”, “lower half of β5 helix” and “helix of Cε2” are missing articles; i.e., “a helix”, “a β5-helix joint”, “the lower half of a β5” and “a helix of Cε2”.
In each of claims 9-12 and 14-16, the term “Cε2” is missing an article; i.e., “the Cε2”.
In claim 11, line 2, “helix of Cε2” should be “the helix of Cε2”. Compare with claim 9, line 2.
In each of claims 14-16, the terms “β3 region” (claim 14), “β4 region” (claim 15) or “β3 or β4 region” (claim 16) are each missing an article; i.e., “a β3 region”, “a β4 region” or “a β3 or β4 region”.
In claim 18, line 2, “Fab2” should be “F(ab’)2”.
In claim 30, line 2, “IgE protein” should be “IgE antibody”.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
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 6, 8-16, 21 and 29-30 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 6 recites the limitation “the antigen binding polypeptide” in line 1. There is insufficient antecedent basis for this limitation in the claim. Specifically, claim 6 depends from claim 1, which does not contain any reference to “an antigen binding polypeptide” to provide antecedent basis for the recitation in the dependent claim.
Claim 8 recites the limitation “the Cε2” in line 2. There is insufficient antecedent basis for this limitation in the claim. Specifically, claim 8 depends from claim 1, which does not contain any reference to “a Cε2” to provide antecedent basis for the recitation in the dependent claim. This could be corrected by amending the claim, for example to recite “a Cε2 domain of the IgE”.
Claim 13 recites the limitation “the β5-Cε2 region” in line 2. There is insufficient antecedent basis for this limitation in the claim. Specifically, claim 13 depends from claim 8, which does not contain any reference to “a β5-Cε2 region” to provide antecedent basis for the recitation in the dependent claim. Instead claim 13 refers to “a β5-helix region”. If reference to this is intended, the antecedent basis could be corrected, for example, by amending claim 13 to refer to “the β5-helix region”.
Claim 21 recites “at least one [CDR] select from SEQ ID Nos 51-200”. This recitation is indefinite with respect to SEQ ID NO: 151-175, because each of these sequence identifiers is empty (“000”), with no associated sequence, in the most recent sequence listing (filed on 2/22/24), and therefore it is not clear what amino acid sequence is being recited by the claim.
Claim 29, lines 2-3, recites “a light chain variable region selected from SEQ ID Nos 209-212”; however, SEQ ID NO: 209-212 appear to be full-length light chain sequences. Compare with claim 28, line 2, “a light chain full sequence selected from SEQ ID Nos 209-212”.
Claim 30 recites the limitation “the polypeptide” in line 2. There is insufficient antecedent basis for this limitation in the claim. Specifically, claim 30 depends from claim 1, which does not contain any reference to “a polypeptide” to provide antecedent basis for the recitation in the dependent claim.
The remaining claim(s) included in the rejection are dependent claims that depend from one of the claims rejected above, and encompass the same indefinite subject matter.
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 1-25, 27-28 and 30 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.
Per MPEP 2163, 35 U.S.C. 112(a) requires, “separate and distinct from the enablement requirement”, that the “specification shall contain a written description of the invention…” (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1 336, 1355 (Fed. Cir. 2010)). In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicants are claiming and what Applicants have possession of.
The instant claims are directed to a product that is an antibody, or fragment thereof, comprising a Fab region that specifically binds to an IgE (immunoglobulin E), wherein the binding of the Fab disrupts interaction between the IgE and at least one Fcε receptor. The product is defined structurally as being an antibody (a structure comprising two protein chains composed of amino acids) and functionally as (1) specifically binding to IgE and (2) disrupting interaction between the IgE and a Fcε receptor.
The prior art recognizes that antibodies bind to epitopes of 5-7 amino acids (Benjamini et al, 1991. Immunology: A Short Course, 2nd edition, page 40 only). Immunoglobulin E (IgE) is hundreds of amino acids in length (as evidence by dependent claim 12, which refers to threonine 298). Thus, even considering only continuous epitopes, IgE comprises a multitude of different regions of five amino acids that can serve as epitopes; i.e., residues 1-5, 2-6, 293-298, etc. While the general structure of an antibody was well-known in the prior art, it is the structure of the complementarity-determining regions (CDRs) that determines the specificity of a particular antibody, and said CDR structure is not predictable based on the epitope to which it binds. Thus, even knowing the structure (CDRs) of one antibody does not allow the skilled artisan to predict the structure of other antibodies that bind to the same epitope or to the other epitopes in the same protein. The relevant art, Ferrara et al (2015. mAbs. 7(1): 32-41) teaches that there is substantial variation in the structure of antibodies that bind to a single protein, on the order of hundreds of different sequences; specifically, see page 36: "The number of different HCDR3s selected against the test antigens ranges from 74 to 460 (Table 3), with the actual number of different antibodies likely to be significantly higher when different VL chains and additional VH mutations are taken into account” (pg 36). Thus, there are at least hundreds of different antibody structures that bind to IgE.
Thus the claims are genus claims, because they are directed to a genus of antibodies having different amino acid sequences but sharing the same functionality.
A product defined by function is not in and of itself sufficient to describe the product because it is only an indication of what the product does, rather than what it is; i.e., the specific structure of the product. It is only a definition of a useful result rather than a definition of what achieves that result. Per MPEP 2124, "describing a composition by its function alone typically will not suffice to sufficiently describe the composition". Furthermore, in the instant case the specification does not establish a correlation between structure and function; e.g., the structure of one anti-IgE antibody does not provide predictability regarding the range of other compound structures having the same functionality. Furthermore, the decision of the Federal Circuit in Amgen v. Sanofi, 872 F.3d 1367 (Fed. Circ. 2017) held that a claim directed to an antibody requires written description of the antibody itself rather than being satisfied solely by a written description of the antigen to which it binds (the so-called "newly characterized antigen" test). Thus, a description of the target protein (e.g. IgE) is not in and of itself sufficient to provide a description of the genus of antibodies binding IgE and disrupting interaction with a receptor for IgE.
Written description for a genus may also be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, in an unpredictable art, adequate description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Also, “[w]hen a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)). “[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” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69).
The specification provides several working examples in support of the claimed invention. The specification teaches that “24 clones against Cε2 were isolated from a rabbit Fab library” (¶ 110) and that “[a]ll of these clones competitively inhibited the binding of human IgE to FcεRI” (¶ 111). “Cε2” is well-known in the prior art as the second of four constant region domains of IgE (e.g., see page 4 of Hirano et al, 2018. Scientific Reports. 8: 14237, 8 pages as printed). The CDRs of these 24 clones are presumably shown in the table on page 64 of the specification; however, the contents of this table are illegible (as set forth in the objections to the specification). The specification teaches that three of these clones were selected from further characterization, which revealed “especially the latter half of the β5-helix region was the essential portion for the inhibitory binding” and that “These Fabs competitively inhibited the binding of human IgEs to human CD23, and removed IgEs bound to CD23” (¶ 111). The characterization of the three selected Fabs is described in Examples 1-10.
Even if the initial 24 clones were demonstrated to be those of the table on page 64, disclosure of the CDR sequences of 24 antibodies is not sufficient to describe the genus of antibodies binding to IgE and inhibiting its interaction with an Fcε receptor, as this genus is expected to encompass at least hundreds of different members, as evidenced by the teaching of Ferrara set forth above. Furthermore, the disclosure of the three antibodies that bind to a region of Cε2 of IgE is not sufficient to describe the subgenus of antibodies that bind to such as region (as recited in dependent claim 8) or to specific parts of such a region (as recited in dependent claims 9-13). The disclosure of these three antibodies does not provide any description of other antibodies that are encompassed by the invention, which must instead be isolated by further screening. Per MPEP 2163, "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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")
With respect to dependent claim 18, this claim limits the antibody to various types of antibody or antibody fragments. However, this group includes a single-domain antibody (sdAb) and a camelid antibody, each of which consists of only a single antibody chain having three CDRs. However, the specification fails to provide any description of any single chain antibody sequences, defined by sequence, that have the ability to bind to IgE. All of the disclosed antibodies have two chains, heavy and light. As such, the specification lacks a written description of the scope of antibodies encompassed by claim 18.
With respect to dependent claims 19-21, 24-25 and 27-28, these claims further limit the antibody by defining a portion of the structure; specifically, by requiring the antibody to have one defined heavy chain sequence (claims 19, 24 and 27); or one defined light chain sequence (claims 20, 25 or 28); or one defined CDR sequence (claim 21). However, each claim encompasses antibodies that comprise less than a full set of six defined CDRs that have been shown to function together to produce an antigen-binding site that will bind IgE. As such, the claims broadly encompass antibodies in which only one, two, three, four or five of the six CDRs is defined by amino acid sequence, and the specification does not describe a representative number of other CDR sequences that function together with each of the defined sequences to form the requisite antigen-binding site. As such, the specification lacks a written description of the scope of antibodies encompassed by each of claims 19-21, 24-25 and 27-28.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “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” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116).
Therefore, only an antibody or a fragment thereof, comprising a Fab region that specifically binds to an IgE, wherein the binding of the Fab to the IgE disrupts interaction between the IgE and at least one Fcε receptor, wherein the Fab region comprises a set of six defined CDRs, e.g., the six CDRs of the elected species, which are an HCDR1 of SEQ ID NO: 70, an HCDR2 of SEQ ID NO: 95, an HCDR3 of SEQ ID NO: 120, an LCDR1 of SEQ ID NO: 145, an LCDR2 of RAS and an LCDR3 of SEQ ID NO: 195, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112(a). Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg 1115).
Note on Prior Art Rejection(s)
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-11, 17-18, 22-23 and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Adams, U.S. Patent Application Publication 20190144565, published 5/16/19. The earliest date to which the instant application claims priority is 10/7/22.
Claim 1 encompasses an antibody comprising a Fab region that specifically binds to an IgE (Immunoglobulin E), wherein the binding of the Fab to the IgE disrupts interaction between the IgE and at least one Fcε receptor.
Adams teaches “improved anti-IgE antibodies” with improved “interaction with the Cε2 domain of IgE” and “ability to disassociate IgE from the FcεRI receptor” (¶ 1). Adams teaches that the antibody may be a Fab fragment (¶ 91). Thus, Adams teaches an antibody comprising a Fab region that specifically binds to IgE and disrupts interaction between the IgE and at least one Fcε receptor. As such, the teachings of Adams anticipate claim 1.
Claim 2 encompasses an antibody of claim 1 wherein the disrupted interaction comprises blocking an unbound IgE from binding to the at least one Fcε receptor. Adams further teaches that with respect to “omalizumab Fab3”, which is one of the anti-IgE Fabs of the invention, “increasing concentrations of omalizumab Fab3 inhibited binding of IgE-Fc to FcεRIα” (¶ 401). As such the teachings of Adams also anticipate claim 2.
Claim 3 encompasses an antibody of claim 1 wherein the disrupted interaction comprises dissociating a bound IgE from the receptor. The teachings of Adams set forth above that anticipate claim 1 are directed to an antibody that dissociates IgE from an FcεRI receptor. As such, these teachings also anticipate claim 3.
Claim 4 encompasses an antibody of claim 1 wherein the disrupted interaction results in suppression of degranulation. Degranulation is an inherent results of IgE binding to an Fcε receptor; as such, any antibody that blocks such binding will suppress the result of such binding; i.e., degranulation. As such, the teachings of Adams that anticipate claim 1 also anticipate claim 4.
Claims 5-7 encompass an antibody of claim 1, wherein the receptor comprises FcεRI (claim 5), CD23 (claim 6) or both. The teachings of Adams that anticipate claim 1 are directed to a receptor that is FcεRI, and Adams further teaches that antibodies of the invention inhibit binding to both FcεRI and CD23 (e.g., at ¶ 382). As such, the teachings of Adams also anticipate claims 5-7.
Claim 8 encompasses an antibody of claim 1, wherein the Fab region specifically binds to at least one amino acid residues in β5-helix region of the Cε2, wherein this region is the combination of helix, β5-helix joint and lower half of β5 that connects to helix of Cε2. This region is not further defined by the specification; i.e., no specific amino acids are designated as being the boundaries of this region, but Figure 8 shows specific amino acids labeled as “β5” and “Helix”. Thus, any of the amino acids shown in Figure 8, including T298, are encompassed by the amino acid of this claim. Adams further teaches that an antibody of the invention may contact an epitope that includes T298 (¶ 9; claim 4).
Claims 9-11 encompass an antibody of claim 8, wherein the Fab region specifically binds to at least one amino acid residue in the helix of Cε2 (claim 9), the β5-helix joint of Cε2 (claim 10) or the lower half of t β5 that connect to the helix of Cε2 (claim 11). The instant specification does not provide any specific definitions (i.e., identify specific residues) of these terms, and as such each is interpreted broadly as encompassing any amino acids shown in the region shown in Figure 8, including T298. As such, the teaching of Adams that anticipates claim 8 also anticipates claims 9-11.
Claims 17 and 18 encompass an antibody of claim 1 wherein the antibody is bispecific (claim 17) or a Fab’ fragment (claim 18). Adams further teaches that the anti-IgE antibody can be a Fab’ fragment or bispecific (e.g., ¶ 90). As such, the teachings of Adams also anticipate claims 17 and 18.
Claim 22 encompasses an antibody that exhibits a KD of less than 2 nM. Adams further teaches, in Table 5, three anti-IgE antibodies of the invention with a KD of less than 2 nM. As such, the teachings of Adams also anticipate claim 22.
Claim 23 encompasses an antibody of claim 1 that is humanized. Adams further teaches that the anti-IgE antibody can be humanized (e.g., at ¶ 102). As such, the teachings of Adams also anticipate claim 23.
Claim 30 encompasses a complex comprising an antibody of claim 1 bound to IgE. Adams further teaches “complexed IgE-Fc/anti-IgE antibody” (e.g., at ¶ 12). As such, the teachings of Adams also anticipate claim 30.
Conclusion
Claim 26 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674
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