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 .
Claim Status
Applicant’s preliminary amendments and remarks, filed 06/25/2024, are acknowledged.
Claims 2-17 are canceled.
Claim 1 is pending.
As such, claim 1 is pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/25/2024 and 10/09/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: Fig. 7 displays a line graph and table referencing “#1”, “#2”, and “Mean”, however the description does not describe what “#1” and “#2” represent.
Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. 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). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The drawings are objected to because Fig. 24E recites “Ab5H5/Ab5L FP16”, however the description recites “Ab5H/Ab5L FP16”.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. 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). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 specification (e.g., page 303) are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, 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 lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The disclosure is objected to because of the following informalities:
Page 97: add a period after “MT-SP1 treatment”.
Page 98: “As inactive molecule” should read “As an inactive molecule”.
Para. [0537]: add a period after “(Figs. 22A, 23A and 24A)”.
Appropriate correction is required.
The use of the term Biacore, Expi293, MabSelect SuRe, GE Healthcare, Superdex, Charles River Laboratories, Promega, Xevo, Acquity, Masslynx, Phoenix WinNonlin, GloMax, Microsoft, Excel, GraphPad Prism, Sigma, Gibco, Corning, Matrigel, Qiagen, MSD, Meso Scale Discovery, Roche, R&D Systems, Molecular Devices, Softmax Pro, Abcam, Cytiva, TSKgel, Tosoh, Biolegend, ATCC, Applied Biosystems, Genscript, Luna, Thermo Scientific, and MultiSkan, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (i.e., pages 329 and 348). 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 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.
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The phrase “is promoted by” renders the claim indefinite because it is unclear what is meant by the phrase. While the claim indicates that the dissociation of the protease cleavage site is promoted by at least one amino acid modification performed at the interface, it is unclear whether the amino acid modification is what causes the dissociation or if the dissociation of the protease cleavage site results in an amino acid modification.
Further, the phrases “is promoted by” and “performed at” make the claim indefinite because the limitation indicates a method step, thus it is unclear whether Applicant is claiming a composition or a method of modifying the composition.
The term “corresponding interacting domain” in claim 1 is a relative term which renders the claim indefinite. The term “corresponding interacting domain” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically, it is unclear whether the “corresponding interacting domain” is the antigen-binding domain previously described, or if it is a completely different domain within the polypeptide. As such, the scope of the invention is unclear.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “is an antibody”, and the claim also recites “monovalent or bivalent, monospecific or bispecific, or an IgG antibody selected from the group consisting of IgG1,IgG2, IgG3, IgG4, IgG-IgG, IgG-Fab, or CrossMab antibody” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “is an antibody fragment”, and the claim also recites “scFv, scFv-Fc, tandem scFv, Fab, tandem Fab, F(ab')2, Fab2, Fab-scFv-Fc, F(ab')2-scFv2, bispecific Fab2, trispecific Fab2, bispecific diabody, trispecific diabody, tandem diabody, triabody, tetrabody, minibody, bibody or tribody” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Further, the scope of the antibodies and antibody fragments are overlapping. For example, the claim recites “IgG-Fab”, “Fab”, and “tandem Fab”; “Fab2”, “bispecific Fab2”, and “trispecific Fab2”; and “scFv”, “scFv-Fc”, “tandem scFv” which overlap in scope. As such, claim 1 is rejected.
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.
Claim 1 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 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to a polypeptide comprising at least one antigen-binding domain comprising a protease cleavage site, whereupon cleavage at the protease cleavage site, an antibody domain adjacent to the protease cleavage site dissociates and wherein the dissociation is promoted by at least one amino acid modification performed at the interface between said antibody domain and a corresponding interacting domain, wherein the polypeptide is an antibody that is monovalent or bivalent, monospecific or bispecific, or an IgG antibody selected from the group consisting of IgG1,IgG2, IgG3, IgG4, IgG-IgG, IgG-Fab, or CrossMab antibody; or wherein the polypeptide is an antibody fragment, the antibody fragment is selected from the group consisting of scFv, scFv-Fc, tandem scFv, Fab, tandem Fab, F(ab')2, Fab2, Fab-scFv-Fc, F(ab')2-scFv2, bispecific Fab2, trispecific Fab2, bispecific diabody, trispecific diabody, tandem diabody, triabody, tetrabody, minibody, bibody or tribody.
The specification disclose of IL-12 fusion proteins having protease cleavable linkers in order to deliver cytokines (see Example 1). The IL-12 fusion proteins remain in an inactivated state until otherwise exposed to an environment with high concentrations of proteases which activates the protein by cleaving the protease cleavage site within the protein; once cleaved, IL-12 no longer binds to the protein, restoring its physiological activity to bind to its receptor and becomes capable of exerting its biological activity to activate IL-12 receptor signaling (see [0467]). The specification disclose that the IL-12 fusion protein in the uncleaved state (inactive) has a long systemic half-life compared to recombinant IL-12 alone; however, when cleaved (active), the IL-12 fusion protein will demonstrate a faster half-life than recombinant IL-12 (see Fig. 1).
Several of the IL-12 fusion proteins were constructed by fusing IL-12 molecules, comprising the p40 and p35 subunits, with IgG-like polypeptides that bind IL-12 via protease-cleavable linkers (see [0468]). Further, unless otherwise noted, modifications were performed in the Fc region of said protein that abolishes Fc gamma R binding, comprising amino acid mutations L235R/G236R according to EU numbering (see [0468]). Three IL-12 fusion proteins, each comprising a monovalent heterodimer of a polypeptide comprising an IL-12 binding domain (anti-IL-12) and a polypeptide comprising a KLH binding domain (anti-KLH) (see [0469]).
In its inactivated form, the IL-12 ligand binds to the ligand-binding domain of the fusion protein, i.e. the IL-12 ligand, binds to the variable region of the fusion protein and the biological activity of the ligand to bind its ligand receptor is inhibited (see Example 3). In a particular example, upon cleavage by protease in the targe tissue environment, the protease cleavage site near the boundary of VH and CH1 is disrupted, resulting in the release of VH (see [0497]). The release of VH in turn disrupts the binding between IL-12 and the ligand-binding domain of the fusion protein, thus releasing the IL-12 (see [0497]). To break any remaining avidity between VH domain and VL domain that may affect the release of IL-12, engineering of the interface between VH and VL was performed to reduce the association between VH and VL (see [0498]). Predominantly amino acids in the FR regions making up the VH/VL interface have been modified to increase VH release tendency after protease cleavage; further, the inventors also discovered that additionally modifying amino acid(s) within the CDR region was able to promote dissociation of VH without disrupting IL-12 binding to the variable region of the IL-12 fusion protein (see [0498]). VH release promoting amino acid modifications were done at either one or more sites of V37, G44, L45, W47, Y91, W103 of Ab101H VH (SEQ ID NO: 1011) and A43, P44, L46, Y49, Y87 and F98 of Ab102 VL (see [0500]; Tables 8, 9, 11A, 11B, 12, and 13).
Additionally, the specification discloses of three IL-22 fusion proteins FP14, FP15 and FP16, each with a different molecular format (see [0537]; Figs. 22A, 23A, and 24A; Table 17A-17C).
However, the specification fails to disclose Applicant’s possession of the large genus of polypeptides as claimed. Specifically, the specification fails to disclose that Applicant was in possession of a large genus of polypeptides comprising at least one antigen-binding domain comprising any protease cleavage domain and any antibody domain. The specification also fails to disclose that Applicant was in possession of a large genus of interacting domains.
Although the specification discloses of IL-12 and IL-22 fusion proteins, the claims are not limited to these polypeptides, and are inclusive of any polypeptide comprising at least one antigen-binding domain comprising any protease cleavage domain and any antibody domain. This indicates that there are hundreds, if not thousands, of possible polypeptides encompassed by the claims. Thus, the claims encompass a vast genus of polypeptides that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of polypeptides because, inter alia, the specification does not disclose a correlation between the necessary structure of the polypeptide and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Although the term antibody does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies/therapeutic agents and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of polypeptides. The disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
The instant claims do not fully describe the structure of the protease cleavage site or antibody domain to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of polypeptides, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous polypeptides had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of polypeptides claimed only by a partial structure and functional characteristic(s). Thus the polypeptides described by the instant claims encompasses an overly broad genus, the structure of the protease cleavage site and antibody domain, and the functional outcome.
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), it is noted that to show invention, a patentee must convey in its disclosure that is “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). 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). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of polypeptides by the components within it (e.g., an antigen-binding domain comprising a protease cleavage site or an antibody domain adjacent to the protease cleavage site). As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "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." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed polypeptides that are antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation 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. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine residue at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed polypeptides could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of proteins, an 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 (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all polypeptides.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed polypeptides. 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, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of polypeptides as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Igawa et al (US 2020/0207846 A1, publication date: 07/02/2020; priority date: 11/28/2017).
The applied reference has a common assignee and applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Igawa et al is drawn to a ligand binding molecule whose ligand binding activity is attenuated by the cleavage of a cleavage site and a method for producing the same, a complex formed by the ligand binding molecule and a ligand, a fusion protein comprising the ligand binding molecule and a ligand, and a pharmaceutical composition comprising the ligand binding molecule or a fusion protein of the ligand binding molecule and a ligand (see Abstract). Specifically, Igawa et al disclose that the ligand binding molecule is a polypeptide having at least one cleavage site and an antibody VH, antibody VL, and an antibody constant region (see claims 1-4). Igawa et al disclose that the cleavage site or the protease cleavage sequence is located near the boundary between the antibody constant region and the antibody VH and/or near the boundary between the antibody constant region and the antibody VL (see claim 5). Further, Igawa et al disclose that the protease cleavage site and a linker are inserted near the boundary between the antibody heavy or light chain constant region and/or the antibody VH/VL, respectively (see claim 18). Igawa et al disclose that the ligand binding molecule is an IgG antibody (see claim 9).
As such, the teachings of Igawa et al anticipate the present invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
12,030,955 B2
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 14-17 of U.S. Patent No. 12,030,955 B2 (patent date: 07/09/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘955 patent is drawn to a polypeptide comprising an antigen-binding domain and a carrying moiety, wherein the carrying moiety has an inhibiting domain that inhibits the antigen-binding activity of the antigen-binding domain, wherein the polypeptide has a protease cleavage sequence comprising one or a plurality of sequences selected from the sequences of SEQ ID Nos: 168-177, wherein the antigen-binding domain comprises a single-domain antibody and has a shorter half-life in blood than the carrying moiety (see claim 1). The ‘955 patent is drawn to the protease cleavage sequence cleaved by a protease so that the antigen-binding domain becomes capable of being released from the polypeptide or/and so that the association of the inhibiting domain of the carrying moiety with the antigen-binding domain is canceled (see claim 5). The ‘955 patent is drawn to the polypeptide of claim 1, wherein the antigen-binding domain comprises a single-domain antibody, wherein the inhibiting domain of the carrying moiety is a VHH, an antibody VH, or an antibody VL, and wherein the antigen-binding activity of the single-domain antibody is inhibited by the VHH, the antibody VH, or the antibody VL (see claim 7). The ‘955 patent is drawn to the polypeptide of claim 1, wherein the carrying moiety comprises an antibody constant region (see claim 8). The ‘955 patent is drawn to the polypeptide of claim 8, wherein the N terminus of the antibody constant region of the carrying moiety and the C terminus of the antigen-binding domain are fused via a linker or without a linker, and wherein the protease cleavage sequence is located near the boundary between the antigen-binding domain and the antibody constant region (see claim 9). The ‘955 patent is drawn to the polypeptide of claim 8, wherein the antibody constant region of the polypeptide is an IgG antibody constant region (see claim 10). The ‘955 patent is drawn to the polypeptide of claim 1, wherein the polypeptide is an IgG antibody-like molecule (see claim 11).
As such, the ‘955 patent anticipates the present application.
12,060,654 B2
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 and 20-23 of U.S. Patent No. 12,060,654 B2 (patent date: 08/13/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘654 patent is drawn to a ligand binding molecule which is a molecule capable of binding to a ligand, wherein the molecule is a polypeptide having at least one cleavage site, and the ligand binding of the molecule cleaved at the at least one cleavage site is attenuated, wherein the ligand is: (a) a cytokine or a chemokine; (b) selected from an interleukin, an interferon, a hematopoietic factor, a member of the TNF superfamily, a chemokine, a cell growth factor, and a member of the TGF-β family; or (c) CXCL10, IL12, PD1, or IL6R (see claim 1). The ‘654 patent is drawn to the ligand binding molecule according to claim 1, wherein the at least one cleavage site comprises a protease cleavage sequence (see claim 2). The ‘654 patent is drawn to the ligand binding molecule according to claim 1, wherein the ligand binding molecule comprises an antibody VH, an antibody VL, and an antibody constant region (see claim 4). The ‘654 patent is drawn to the ligand binding molecule according to claim 4, wherein the cleavage site or the protease cleavage sequence is located near the boundary between the antibody constant region and the antibody VH and/or near the boundary between the antibody constant region and the antibody VL (see claim 5). The ‘654 patent is drawn to the ligand binding molecule according to claim 4, wherein the antibody VL and the antibody VH are associated with each other, and wherein the association is canceled by cleavage of the cleavage site or canceled by the protease cleavage of the protease cleavage sequence (see claim 6). The ‘654 patent is drawn to the ligand binding molecule, wherein the protease cleavage sequence, the protease cleavage sequence and the first flexible linker, or the protease cleavage sequence and the first flexible linker and the second flexible linker is located near the boundary between the antibody constant region and the antibody VH or/and near the boundary between the antibody constant region and the antibody VL (see claim 16).
As such, the ‘654 patent anticipates the present invention.
12,195,528 B2
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 12-13, and 15 of U.S. Patent No. 12,195,528 B2 (patent date: 07/14/2025). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘528 patent is drawn a ligand-binding molecule which is capable of binding to a ligand, wherein the molecule is a polypeptide comprising at least one protease cleavage sequence comprising one or more sequences selected from the sequences shown in SEQ ID Nos: 338, 335, 336, 337, 339-344, and 538-1145 wherein the binding of the ligand-binding molecule to the ligand in a state where the protease cleavage sequence is cleaved is weaker than the binding of the ligand-binding molecule to the ligand in a state where the protease cleavage sequence is uncleaved, and wherein the ligand is: (a) a cytokine or a chemokine; (b) selected from an interleukin, an interferon, a hematopoietic factor, a member of the TNF superfamily, a chemokine, a cell growth factor, and a member of the TGF-β family; or (c) CXCL10, IL12, PD1, or IL6R (see claim 1). The ‘528 patent is drawn to the ligand-binding molecule of claim 1, wherein the ligand is bound, complexed, or fused to the ligand-binding molecule in a state where the protease cleavage sequence is uncleaved, and wherein the ligand is released from the ligand-binding molecule in a state where the protease cleavage sequence is cleaved (see claim 2). The ‘528 patent is drawn to the ligand-binding molecule of claim 1, which comprises an antibody VH, an antibody VL, and an antibody constant region (see claim 4). The ‘528 patent is drawn to the ligand-binding molecule of claim 4, wherein the protease cleavage sequence is located near the boundary between the antibody constant region and the antibody VH, and/or near the boundary between the antibody constant region and the antibody VL (see claim 5). The ‘528 patent is drawn to the ligand-binding molecule of claim 4, wherein the antibody VL and the antibody VH in the ligand-binding molecule are associated with each other, and the association is eliminated by cleavage of the protease cleavage sequence with the protease (see claim 6). The ‘528 patent is drawn to the ligand-binding molecule of claim 1, wherein the ligand-binding molecule is an IgG antibody (see claim 8). Lastly, the ‘528 patent is drawn to a fusion protein comprising the ligand-binding molecule of claim 1 fused with the ligand (see claim 12).
As such, the ‘528 patent anticipates the present invention.
12,655,220 B2
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 7-14 of U.S. Patent No.12,655,220 B2 (patent date: 06/16/2026). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘220 patent is drawn to a fusion protein which comprises a ligand-binding moiety and is represented by formula (I): [Ligand-binding domain] -[Lx]- [Cx] -[Ly]- [Ligand moiety] (I) wherein: Lx represents a first peptide linker comprising a first protease cleavage site; Cx represents a constant region comprising a second peptide linker and one or more amino acid residues which are modified from or to cysteine; Ly represents a third peptide linker, and wherein the ligand-binding domain comprises a VH region and a VL region, binds to the ligand moiety, and is capable of releasing the ligand moiety in the presence of a protease, wherein the constant region comprises an antibody heavy chain comprising a CH1 region and an Fc region and an antibody light chain comprising a CL region, (a) wherein the second peptide linker is positioned in a hinge region so that disulfide bond formation between Cys at position 220 of the heavy chain and Cys at position 214 of the light chain is promoted, with all positions according to EU numbering; (b) wherein amino acid residues in the heavy chain and the light chain are modified so that no disulfide bond is formed between position 220 of the heavy chain and position 214 of the light chain, with all positions according to EU numbering; or (c) wherein the heavy chain is modified to allow disulfide bond formation between position 131 of the heavy chain and position 214 of the light chain, with all positions according to EU numbering; and wherein the first protease cleavage site of Lx is located between the VH or VL region and the CH1 or CL region, respectively (see claim 1). The ‘220 patent is drawn to the fusion protein of claim 1 or 2, wherein the fusion protein comprises a full-length antibody (see claim 8). The ‘220 patent is drawn to the fusion protein of claim 1, wherein Lx comprises more than one protease cleavage site which is located between the VH or VL region and the CH1 or CL region (see claim 9). Lastly, the ‘220 patent is drawn to the fusion protein of claim 1 or 2, which further comprises a second protease cleavage site, wherein the ligand moiety is connected to an N-terminal region of the ligand binding moiety via the second protease site (see claim 11).
As such, the ‘220 patent anticipates the present invention.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford can be reached at (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
Prosecution Insights