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 .
Application Status
The amended claims filed December 4, 2023 are entered. Claims 2-7, 9, 11-21, 24, 26, 30-36, 38-49, 52, 54-55, 57-58, 60, 62-65, 67-83, 85-112, 115, 118-121, 123, 125, 127-139, 141-146, 149-167, 170-171, 173-178, 181-182, 184-195 are canceled. Claims 8, 10, 22, 25, 37, 50-51, 53, 59, 61, 66, 84, 113-114, 122, 124, 126, 140, 147, 168-169, 172, 179-180, and 183 are amended.
Claims 1, 8, 10, 22-23, 25, 28-29, 37, 50-51, 53, 56, 59, 61, 66, 84, 113-114, 116-117, 122, 124, 126, 140, 147-148, 168-169, 172, 179-180 and 183 are pending and under examination herein.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). See Figure 21. Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The specification is objected to for the following informalities. Appropriate correction is required.
The figure caption for Figure 20 (page 35) contains references to color (“yellow”, “cyan”, “dark blue”), but the corresponding drawing is in grayscale.
There are two tables which are denoted as Table 1, on page 95 (exemplary amino acid substitutions) and on page 119 (anti-KLK7 antibody off-rates against human and cynomolgus monkey KLK7). Tables in the specification should be labeled numerically in the order they appear. Further, any corresponding in-text citations for each table should be updated as appropriate.
Applicant is reminded that the subject matter of ¶ 009 was deleted in the amendment filed March 8, 2024, and that an amended specification submitted in response to this Office action should have updated paragraph numbers to reflect said amendment.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See pages 46-47, bridging paragraph. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 1, 8, 22-23, 25, 29, 66, 126, 168, and 179 are objected to because of the following informalities:
As presently constructed, claim 1 appears to recite that the anti-KLK7 antibody comprises a heavy chain variable domain (VH) of the antibody that comprises (1) three VH CDRs and (2) a light chain variable domain (VL) comprising three VL CDRs. However, it is understood in the art that a VH does not comprise a VL. The claim would be clearer if, for example, it recited that the antibody comprises a binding domain comprising a VH having a specific combination of three CDRs and a VL having a specific combination of three CDRs, such as in claim 56. Claim 1 should be amended for clarity. (Claims 8, 10, 22-23, 25, 126, 168, and 179, which depend from claim 1, are similarly objected to.)
It is suggested that claim 8 should be amended to recite, in list item (a), “…a VH sequence having at least 95% sequence identity to an
Claim 29 recites that the CDR-L1 comprises the amino acid sequence of “SEQ ID NOs: 43,” in list item (d), where “SEQ ID NOs” would suggest more than one possible sequence, but only one follows. It is suggested that claim 29 be updated to recite “SEQ ID NO: 43”.
The list items (d) and (e) in claim 66 should be updated (to “c” and “d”, respectively) so that the list items are in consecutive order.
Appropriate correction is required.
It is also generally noted that throughout the claims, the claim construction alternates between the use of “SEQ ID NO:” and “SEQ ID NOs:” to refer to multiple possible sequences. In addition, in some instances there is a space between “SEQ ID NO:” and the corresponding number (e.g., “SEQ ID NOs: 15-30 and 202” in claim 8, list item (a)), while in others there is not (e.g., “SEQ ID NO:31-38” in claim 8, list item (b)). It is encouraged that the Applicant apply consistent formatting throughout the claims.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 37 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 37 recites the anti-KLK5 antibody of claim 28, wherein the VL comprises an amino acid sequence selected from SEQ ID NO: 51 and 54-67. However, the independent claim 28 requires that the VL comprise a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43 or 44, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47. The VL sequences corresponding to SEQ ID NO: 51, 54, 56, 58-61, 63, and 65-67 do not comprise all three of the required CDR amino acid sequences (in particular, the CDR-L3 comprising an amino acid sequence of SEQ ID NO: 47 or “AQGYGSSGVENV”). Consider, for example, Figure 2A-3. Accordingly, claim 37 fails to include all of the limitations of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
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 28, 37, 50-51, 53, 61, 66, 84, 114, 117, 124, 140, 148, 169, and 180 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.
“[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).
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 it may be satisfied by the 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. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
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. Reagents 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 claimed invention. In one aspect, the nature and scope of the claimed invention at issue is an anti-KLK5 antibody (as recited in claim 28 and dependent claims 37, 50-51, 53, 140, 169, and 180) that comprises a heavy chain variable region (VH) comprising three CDRs having the amino acid sequences of SEQ ID NO: 39, 40, and 204, respectively, or SEQ ID NO: 107, 40, and 204, respectively, or SEQ ID NO: 107, 41, and 204, respectively, along with a corresponding combination of three light chain variable region (VL) CDRs. The claims recite combinations of HCDR1, HCDR2, and HCDR3 which are “mixed and matched”. While the instant specification has written description support for an antibody comprising a VH having three CDRs as set forth in SEQ ID NO: 39, 41, and 204, respectively (e.g., as set forth in claim 29), which does have demonstrated binding activity to KLK5 as presently claimed, the disclosure does not provide a showing of exemplary embodiments for the remaining possible combinations of “mixed and matched” HCDRs which also possess the function of binding to KLK5 as required by the instant claims. Furthermore, the disclosure does not provide a sufficient showing that any of the eight possible combinations of LCDRs comprising the amino acid sequences of SEQ ID NO: 43 or 44, 45, and 47, respectively, may be paired with these “mixed and matched” HCDR combinations while possessing the required functional activity of binding to KLK5.
In a second aspect, the nature and scope of the claimed invention at issue is a bispecific antibody comprising a first binding domain that binds to human KLK7 and a second binding domain that binds to human KLK5 (as recited in claim 61 and 66(a-b) and in claims 84, 114, 117, 124, and 148), wherein the anti-KLK5 binding domain comprises a heavy chain variable region (VH) comprising three CDRs having the amino acid sequences of SEQ ID NO: 39, 40, and 204, respectively, or SEQ ID NO: 107, 40, and 204, respectively, or SEQ ID NO: 107, 41, and 204, respectively, along with a corresponding combination of three light chain variable region (VL) CDRs. Similarly to the first aspect above, the claims recite combinations of HCDR1, HCDR2, and HCDR3 amino acid sequences which are “mixed and matched” but do not have written description support in the disclosure as set forth above. Furthermore, the disclosure does not provide a sufficient showing that any of the eight possible combinations of corresponding LCDRs may be paired with these “mixed and matched” HCDR combinations while possessing the required functional activity of binding to KLK5.
The disclosure does include support for anti-KLK5 antibodies having a VL and a VH, wherein the VH comprises a combination of three CDRs having the amino acid sequences of SEQ ID NO: 39, 40, and 42, respectively, or SEQ ID NO: 107, 40, and 42, respectively, or SEQ ID NO: 107, 41, and 42, respectively (corresponding to SEQ ID NO: 50, 105, and 106, shown in Figure 2B).
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) that provide the majority of the contact residues for the binding of the antibody to its target epitope. See Almagro (Frontiers in Immunology (2018) 8: 1751), “The IgG Molecule” (page 3) and Figure 1. Sela-Culang (Frontiers in Immunology (2013) 4: 302) 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). 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).
Gershoni (Biodrugs (2007) 21(3): 145-156) teaches that antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (page 146, Section 1.1). The skilled artisan therefore understands that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence.
To summarize, the state of the art demonstrates that a full complement of heavy chain and light chain CDRs together confer antigen-binding properties, and that even minor differences (i.e., single amino acid substitutions) in the binding regions of an antibody can have unpredictable effects on antigen-binding ability. Where the state of the art is unpredictable, Applicant must provide a clear showing that a relationship between a specifically claimed structure (i.e., a specific combination of heavy chain CDRs and light chain CDRs) and function (i.e., binding to an antigen such as KLK5) exists.
Exemplary antibodies that specifically bind to KLK5 have been described previously by Chiu (WO 2019/178316 A1; cited in IDS), Puzer (WO 2021/226695 A1; cited in IDS), and Dedi (WO 2021/156171 A1).
Scope of species disclosed in original specification. The working examples describe the affinity optimization of anti-KLK5 antibodies “hu.9H5.L4H14” and “hu.10C5.L5H28” (e.g., Example 3 at pages 123-125; Figures 4-5), and the incorporation of selected anti-KLK5 antigen-binding domains into bispecific antibody constructs (e.g., Example 4 at pages 125-129).
The disclosure states that five mutations in the “hu.10C5.L5H28” antibody resulted in significantly lower off-rate, corresponding to variants having a VL amino acid sequence of SEQ ID NO: 54, 55, or 56 (containing a substitution in LCDR1, LCDR3, or LCDR3, respectively, numbered according to Kabat), or a VH amino acid sequence of SEQ ID NO: 105 or 52 (containing a substitution in HCDR1 or HCDR2, respectively, numbered according to Kabat) (page 123; Figure 2). Nine specifically tested variants of the “hu.10C5.L5H28” antibody with specific combinations of these optimized substitutions, most of which further comprise Q38E/Q39K substitutions to reduce mispairing of the heavy and light chains (see page 92), are set forth in Tables 6-7 (pages 124-125).
The disclosure further sets forth that four mutations in the “hu.9H5.L4H14” antibody resulted in slower off-rates, corresponding to variants having a VL amino acid sequence of SEQ ID NO: 88 or 89 (each containing one LCDR3 substitution, numbered according to Kabat), or a VH amino acid sequence of SEQ ID NO: 81 or 82 (containing a substitution in HCDR2 and HCDR3, respectively, numbered according to Kabat) (page 123; Figure 3). Ten specifically tested variants of the “hu.9H5.L4H14” antibody with specific combinations of these optimized substitutions, and further comprising Q38E/Q39K substitutions to reduce mispairing of the heavy and light chains (see page 92), are set forth in Tables 4-5 (pages 123-124).
MPEP § 2163 states that 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. In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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.
As demonstrated by the state of the art, a full complement of heavy chain and light chain CDRs together confer the antigen-binding properties of an antibody, but it is not possible to reliably predict how mutations (even those conferred through affinity maturation) may affect binding of the complete antibody (comprising a VH and a VL). Accordingly, one cannot “mix and match” CDRs as set forth by the present claims absent a clear showing that a relationship between the specifically claimed structures and function(s) exists. Furthermore, specific embodiments with the recited heavy chain CDR combinations of SEQ ID NO: 39, 40, and 204, respectively, or SEQ ID NO: 107, 40, and 204, respectively, or SEQ ID NO: 107, 41, and 204, respectively) do not have adequate written description support, such that one of ordinary skill in the art would recognize that these specifically claimed embodiments also possess the required function of binding to human KLK5 based on the disclosure as filed.
Conclusion. For the reasons presented above, one of skill in the art would not know which of the anti-KLK5 antibodies encompassed by the structural requirements of the claims would also possess the required functional activity. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of anti-KLK5 antibodies as broadly claimed at the time the application was filed.
Allowable Subject Matter
Claims 56, 59, 113, 116, 122, 147, 172, and 183 are allowed.
The instantly claimed bispecific antibody comprising a first binding domain which binds to human KLK7 and a second binding domain which binds to human KLK5, wherein the anti-KLK7 binding domain comprises one of the specific combinations of heavy chain and light chain CDRs set forth in claim 56, appears to be free of the prior art. At the time of filing of the instantly claimed invention, it was recognized that KLK7 (also called “SCCE”) and KLK5 (also called “SCTE”), two members of the kallikrein-related peptidase family, were implicated in the etiology of Netherton syndrome and other skin-related ailments, and that simultaneous targeting of both proteases is an effective therapeutic avenue for Netherton syndrome. See, for example, Kasparek (PLOS Genetics (2017) DOI:10.1371/journal.pgen.1006566; cited in IDS). However, few multispecific antibodies or combination antibody therapies targeting KLK7 and KLK5 appear to have been described in the prior art. Tazi-Ahnini (US 2008/0292615 A1) discloses methods of treating diseases such as atopic dermatitis and lung atopic asthma by administering an anti-SCCE (KLK7) antibody or an anti-SCTE (KLK5) antibody (e.g., claims 1-8; Example E6, ¶ 0749-0755). However, Tazi-Ahnini does not disclose or suggest an antibody (monospecific or bispecific) against KLK7 comprising a specific combination of heavy chain and light chain CDRs as that set forth in the instant claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm EST.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643