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 .
Applicant’s amendment, filed on 6/18/2063, is acknowledged.
Claims 1-164 are cancelled.
Claims 165-222 are currently pending.
Claims 165, 187, 192, 201, and 220 are independent claims.
Election/Restrictions
Applicants’ election without traverse of Group I, claims 165-186, 201-219, directed to a peptide complex comprising a transferrin receptor-binding peptide and a complexed target binding peptide, and the Species of: i) the peptide complex sequence of SEQ ID NO: 308; ii) the target of PD-L1; iii) the TfR binding peptide of SEQ ID NO: 96; iv) a cystine-dense peptide miniprotein; v) target binding peptide of SEQ ID NO: 233; and vi) the dimerization domain of SEQ ID NO: 250, filed on 6/18/2026, is acknowledged.
The claimed peptide complex sequence of SEQ ID NO: 308 comprises the PD-L1 targeting peptide of SEQ ID NO: 233, the TfR binding polypeptide of SEQ ID NO: 96, and the homodimerization domain of SEQ ID NO: 250. SEQ ID NO: 233 is a target binding peptide targeting PD-L1, which is a transmembrane immune inhibitory receptor ligand, reading on claims 166, 175, 176, and 204-206.
Additionally, regarding the elected species of SEQ ID NO: 233, the instant specification discloses that this species of target binding peptide has lower affinity to PD-L1 at endocytic pH values (i.e., 5.5) that it does neutral pH values (¶[0405]): “…variant corresponding to SEQ ID NO: 233, containing substitutions at E2H and Kl6H, showed strong binding to PD-L1 at pH 7.4 and substantial loss of binding at pH 5.5…” Therefore, claims 202 and 203 encompass an unelected species of target binding peptide.
Claims 184, 185, 218, and 219 encompass unelected species of dimerization domains (i.e., heterodimerization domain sequences instead of the elected species of domain, which is a homodimerization domain).
Claims 213-215 encompass unelected species of target binding peptides.
Claims 184, 185, 187-200, 202, 203, 207, 213-215, and 218-221 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions and/or Species.
Claims 165-183, 186, 201, 204-212, 216, 217, and 222 are under examination as reading on the elected species of transferrin receptor-binding peptide and a complexed target binding peptide.
Priority
Applicant’s claim for the benefit of a prior-filed U.S. Provisional Application No. 63/119,195, filed on November 30, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/30/2023, 11/28/2023, and 6/18/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner in their entireties.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The use of the terms:
Alexa Fluor® (¶[0063], [0064], [0086], [0365], [0367], [0369], [0400], [0419]);
Nanobody® (¶[0013], [0104], [0114], [0166], [0170], [0213], [0217], [0297], [0309], Example 19, [0422]-[0424], [0431]);
Affibody® (¶[0013], [0166], [0170], [0213], [0217], [0297], [0309]);
Avimer™ (¶[0013], [0166], [0170], [0213], [0309]);
Nanofitin™ (¶[0013], [0166], [0170], [0213], [0217], [0297], [0309]); and
Fynomer® (¶[0013], [0166], [0170], [0213], [0309]);
which are trade names or marks 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.
Please note that any amendments to the Specification must include previously submitted amendments. In the instant case, amendments to the Specification have previously been filed on 5/19/2023.
Claim Objections
Claims 175 and 205 are objected to because the claims each recite the limitations “tumor associated antigen”, tumor specific antigen”, and “an inhibitory immune receptor” twice. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 165-183, 186, 201, 204-212, 216, 217, and 222 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
Claims 165-171, 173-183, and 186, 201, 204-211, 216, 217, and 222 encompass a genus of binding polypeptides with either no recited structure (claims 165-169, 173-183, 201, 204-209, and 216, 217) or a partial structure at best (claims 170, 171, 186, 210, 211, and 222) with the function of “transferrin receptor-binding peptide”. For example, claim 171 encompasses a genus of polypeptides including the elected species of 96 with up to 10% sequence variation. The total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula:
N
!
*
19
A
N
-
A
!
A
!
Where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. For a polypeptide that is 49 residues in length with 4 (49x0.1) allowed substitutions, there would be
49
!
*
19
(
4
)
49
-
4
!
4
!
Which is approximately 9.27x109 variants with the function of “transferrin receptor-binding peptide” for this species alone.
Additionally, claims 165-183 and 186 encompass a genus of peptides with either no recited structure (claims 165-177 and 179-183) or a partial structure at best (claims 178 and 186) with the functions of “target binding peptide” and “target-binding affinity for a target that is lower in an endosome than in an extracellular environment”. For example, claim 178 encompasses peptides comprising the elected species of SEQ ID NO: 233 and up to 10% variation. For a polypeptide that is 49 residues in length with 4 (49x0.1) allowed substitutions, there would be approximately 9.27x109 variants with the functions of “target binding peptide” and “target-binding affinity for a target that is lower in an endosome than in an extracellular environment” for this sequence alone.
Claims 201, 204-212, 216, 217, and 222 encompass a genus of peptides with either no recited structure (claims 201, 204-212, 216, and 217) or a partial structure at best (claim 222) with the function of “target binding peptide”. For example, claim 222 encompasses target binding peptides comprising the elected species of SEQ ID NO: 308 and up to 10% variation. For a polypeptide that is 360 residues in length with 36 (360x0.1) allowed substitutions, there would be approximately 9.27x109 4.42x10135 variants with the functions of “target binding peptide” for this sequence alone.
Furthermore, claims 181-183, 186, 216, 217, and 222 encompass a genus of dimerization domains with either no recited structure (claims 181, 182, 216, and 217) or a partial structure at best (claims 183, 186, and 222) with the recited function of “dimerization domain”. For example, instant claim 183 encompasses homodimerization domain structures including the elected species of SEQ ID NO: 250 with up to 10% sequence variation. For a polypeptide that is 232 residues in length with 23 (232x0.1) allowed substitutions, there would be approximately 9.32x1078 variants with the function of “dimerization domain” for this sequence alone.
However, the specification fails to provide adequate written description support for a genus of polypeptides with a partial structure at best and the function of “transferrin receptor-binding peptide” (claims 165-171, 173-183, 186, 201, 204-211, 213-217, and 222); a genus of peptides with a partial structure at best and the functions of “target binding peptide” and/or “target-binding affinity for a target that is lower in an endosome than in an extracellular environment” (claims 165-183, 186, 201, 204-217, and 222); or a genus of domains with a partial structure at best and the recited function of “dimerization domain” (claims 181-183, 186, 216, 217, and 222).
The claims are not supported by a description that satisfies 35 U.S.C. § 112(a) or 35 U.S.C. § 112, first paragraph. "[T]he test for sufficiency [of the written description] is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Phanns., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane).
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." Id. at 1350. "[A]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials." Id.
"[F]unctional claim language can meet the written description requirement when the art has established a correlation between structure and function." Id. "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 that one has invented a genus and not just a species." Id.
"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) (emphasis added).
The specification discloses screening for peptides that bind for TfR from a large library of peptides with varying amino acid sequences to identify individual structures that have the function of “transferrin receptor-binding peptide” (Example 3): “[t]his example describes mammalian surface display of TfR-binding peptides of the present disclosure…[s]creening for TfR-binding peptides was performed by transfecting or transducing mammalian cells to display candidate peptides (FIG. 9B) followed by screening against soluble human transferrin receptor ectodomain…” ¶[0367]: “…screening strategy used a surface display GFP FasL (SDGF) vector…designed peptides were cloned as a pool into SDGF, which were then made into lentivirus. 293F cells were transduced with this library…[a] percentage of the highest staining TfR-positive cells, from GFP and TfR double-positive cells, were sorted and expanded…the enriched peptides were identified by sequencing.” Site-saturation mutagenesis was used to generate additional polypeptides that bound to TfR (Examples 5 and 6). These TfR-binding polypeptides are disclosed in Table 1.
The specification further discloses specific working examples of polypeptides that bind to PD-L1 (Table 2), and nanobodies that bind to EGFR (Example 19).
The specification further discloses histidine screening of a high-affinity PD-L1 binding polypeptide (SEQ ID NO: 187) to identify specific variant structures that have pH-dependent binding to PD-L1 so that there is lower affinity at a lower pH (Example 9, ¶[0403], [0404]): “…a library of variants was designed containing histidine substitutions…variant library of PD-L1-binding peptides was expressed via mammalian surface display, with each variant containing zero, one or two His substitutions. These variants were tested for maintenance of binding under extracellular pH (such as pH 7.4), and for reduced binding under endosomal pH (such as pH 5.5)…” Peptides with pH dependent PD-L1 binding were identified and disclosed in Fig 22, with emphasis on SEQ ID NO: 233 and (¶[0405]): “[t]he variant corresponding to SEQ ID NO: 233, containing substitutions at E2H and Kl6H, showed strong binding to PD-L1 at pH 7.4 and substantial loss of binding at pH 5.5 (black arrow).”
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520
569
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The specification further discloses protein complexes comprising a transferrin receptor binding peptide and a pH-dependent PD-L1 binding polypeptide (Example 10, ¶[0406]): “…PD-L 1 binding peptides with high PD-L1 binding affinity at physiologic extracellular pH (e.g., pH 7.4) and reduced binding affinity at endosomal pH (e.g., pH 5.5) are fused recombinantly, chemically synthesized as a single fusion, separately recombinantly expressed and conjugated, or separately chemically synthesized and conjugated to a TfR-binding peptide with a TfR-binding affinity that is substantially the same at a physiologic extracellular pH and at endosomal pH ( e.g., a TfR binding peptide of any one of SEQ ID NO: 96, SEQ ID NO: 65 - SEQ ID NO: 95, SEQ ID NO: 97 - SEQ ID NO: 128, SEQ ID NO: 220 - SEQ ID NO: 222, or SEQ ID NO: 1 - SEQ ID NO: 64), optionally with any linker or no linker in between the PD-L1 binding peptide and the TfR binding peptide.” Also see Fig. 12 for an example of this peptide complex (annotated below, polypeptide complex in box):
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394
652
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The specification further discloses one example of a pH-dependent anti-EGFR VHH domain, SEQ ID NO: 243 (Example 19).
The specification further discloses that the polypeptides can be complexed via a linker dimerization domains (Example 24, ¶[0431]): “…receptor-binding peptide is complexed with the target-binding peptide by direct fusion through a linker or by dimerization through a dimerization domain…” Specific heterodimerization domain structures are disclosed in Table 5, while specific homodimerization domain structures are disclosed in Table 6.
With respect to representative number of species, see AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014). Also, see MPEP 2163 Il(A)(3)(a))(ii):
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. 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 Abb Vie 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.").
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
In the instant case, regarding the broadly claimed genera of polypeptides with a partial structure at best and the function of “transferrin receptor-binding peptide” ” (claims 165-171, 173-183, 186, 201, 204-211, 213-217, and 222), the specification discloses a limited number of polypeptide sequences that bind to TfR (Table 1), which does not sufficiently represent the broadly claimed genera of polypeptide structures, defined by their amino acid sequences, that are recited in the claims, which includes millions to billions of different polypeptide structures with the recited function.
Regarding the broadly claimed genera of peptides with a partial structure at best and the recited functions of “target binding peptide” and/or “target-binding affinity for a target that is lower in an endosome than in an extracellular environment” (claims 165-183, 186, 201, 204-217, and 222), the instant specification discloses peptides that bind to PD-L1 in Table 2, and nanobodies that bind to EGFR in Example 19. The instant specification discloses a more limited number of polypeptide sequences that have both of these recited functions. These include pH-dependent PD-L1 binders disclosed in Fig. 22, and the one disclosed pH-dependent anti-EGFR VHH in Example 19. Neither of the limited number of working examples sufficiently represent the broadly claimed genera of polypeptide structures with the functions of “target binding peptide” and/or “target-binding affinity for a target that is lower in an endosome than in an extracellular environment”, which include millions to billions of different structures with these recited functions.
Regarding the broadly claimed genera of peptide domains with the function of “dimerization domain” (claims 181-183, 186, 216, 217, and 222), the limited species of homodimerization and heterodimerization domains disclosed in Tables 5 and 6 do not sufficiently represent the broadly claimed genera of polypeptide structures with both of these recited function, which includes millions to billions of different peptide domain sequences with the recited function.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed genera of peptide structures to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
Given the broadly claimed classes of polypeptide structures with the functions of “transferrin receptor-binding peptide” (claims 165-171, 173-183, 186, 201, 204-211, 213-217, and 222), “target binding peptide” and/or “target-binding affinity for a target that is lower in an endosome than in an extracellular environment” (claims 165-183, 186, 201, 204-217, and 222), or “dimerization domain” (claims 181-183, 186, 216, 217, and 222), and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed classes of polypeptide structures with these recited functions, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014), MPEP 2163.
Regarding the broadly claimed genera of polypeptides with a partial structure at best and the function of “transferrin receptor-binding peptide” (claims 165-171, 173-183, 186, 201, 204-211, 213-217, and 222), the specification that these different polypeptide structure are identified by screening large phage display libraries for specific polypeptide structures that bind to TfR, much like screening for novel antibody structures that bind to a specific epitope. While the instant specification discloses that some of these peptides share some residues that contact TfR (Table 9), neither the instant specification nor the prior art provides sufficient structure-function relationship between a peptide’s amino acid sequence and the function of “transferrin receptor-binding peptide”. The only guidance the instant specification provides is to list individual examples of peptide structures with this function (Table 1).
Regarding the broadly claimed genera of peptides with a partial structure at best and the recited functions of “target binding peptide” and/or “target-binding affinity for a target that is lower in an endosome than in an extracellular environment” (claims 165-183 and 186), neither the instant specification nor the prior art teaches sufficient guidance or a structure-function relationship between a polypeptide’s amino acid sequence and the function of “target binding peptide”. Additionally, the instant specification demonstrates that histidine mutagenesis to generate pH-sensitive target binding polypeptides is unpredictable, with some mutants displaying reduced target binding at a lower pH, while other mutant amino acid sequences do not show any appreciable different in target binding at different pH levels (compare, for example, SEQ ID NO: 233 and 239 in Fig 22 supra). The instant specification does not provide any structure function-relationship between a polypeptide’s amino acid sequence and the claimed functions of “target binding peptide” and/or “target-binding affinity for a target that is lower in an endosome than in an extracellular environment”. The only guidance the instant specification provides is to list individual structure with these functions.
Additionally, the current state of the art teaches that different polypeptide structures, when substituted with the same amino acid at different positions, would lead to unpredictable results in determining pH sensitivity. For example, Sulea et al. (U.S. PGPub 20220162337) teaches that in an anti-Her2 antibody, substituting different CDR residues with histidines sometimes resulted in an antibody that had improved binding at acidic pH values when compared to neutral pH, and also sometimes resulted in an antibody that had reduced binding at pH values when compared to neutral pH (Example 3 and Fig. 3; compare, for example the mutants P2 and P5 to the Parent antibody, which shows decreased affinity at lower pH values):
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678
695
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While some variant antibodies had decreased affinity at a lower pH (see for example, “Parent” and “P2”), other variants had greater affinity at lower pH (“P5”). Thus, even in the current state of the art, there is a great deal of unpredictability between an amino acid’s sequence and its function “target-binding affinity for a target that is lower in an endosome than in an extracellular environment”.
Neither the instant specification nor the prior art provides sufficient guidance or structure-function relationship between a polypeptides structure and the functions of “target binding peptide” and/or “target-binding affinity for a target that is lower in an endosome than in an extracellular environment” to allow one with ordinary skill in the art to “recognize or visualize” additional members of the broadly claimed genera.
Regarding the broadly claimed genera of peptide domains with the function of “dimerization domain” (claims 181-183, 186, 216, 217, and 222), neither the instant specification nor the prior art provides sufficient structure-function relationship between a polypeptide’s sequence and the function of “dimerization domain”. The instant specification only lists specific pairs of heterodimerization domain structure (Table 5), or specific homodimerization domain structures (Table 6) with this recited function. Neither the instant specification nor the prior art provides sufficient guidance to allow one to “visualize or recognize” other polypeptide structures with this recited function.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of polypeptides with the function of “transferrin receptor-binding peptide” (claims 165-171, 173-183, 186, 201-211, 213-217, and 222); a genus of peptides with the functions of “target binding peptide” and “target-binding affinity for a target that is lower in an endosome than in an extracellular environment” (claims 165-183, 186, 201-217, and 222); or a genus of domains with the recited “dimerization domain” (claims 181-183, 186, 216, 217, and 222) falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Claims 165-183, 186, 201, 204-212, 216, 217, and 222 do not meet the requirements of 35 U.S.C. 112(a) for written description.
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.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
To overcome this rejection, it is recommended to amend claims 165 and 201 to recite specific disclosed peptide structures, defined by their amino acid sequences, with the function of “transferrin receptor-binding peptide” (i.e., the structures disclosed in Table 1), as well as specific disclosed peptide structures with the functions of “target binding peptide” and/or “target-binding affinity for a target that is lower in an endosome than in an extracellular environment” (for example, SEQ ID NO: 187, 233, and 234), as well as the target that the structure(s) bind (for example, the elected target of PD-L1). It is further recommended to amend claims 181-183, 186, 216, 217, and 222 to recite specific structures with the function of “dimerization domain” (for example, the elected species of SEQ ID NO: 250).
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 167, 168, 170, 175, 205, 208, and 210 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 167 and 208 contain the trademark/trade names Nanobody® and Affibody®; and claim 168 contains the trademark/trade names Avimer™, Nanofitin™, and Fynomer®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe VHH domains (in the case of Nanobody®), or a target binding polypeptide (in the case of Affibody®, Avimer™, Nanofitin ™, and Fynomer®) and, accordingly, the identification/description is indefinite. To resolve this issue, it is recommended to amend the claims to no longer recite trademarks/trade names.
Claims 170 and 210 contain amino acid sequence identifiers that are directed to amino acid sequences with variable residues SEQ ID NO: 170). It is currently unclear if these variable residues are not limited and can comprise any amino acid, or if the variable residues are limited to a smaller subset of amino acid residues. For the purposes of examination, the claims are interpreted to claim sequences with variable residue positions that can be any amino acid residue. To resolve this issue, it is recommended to amend the claims to recite what amino acid residue(s) can be in each variable position.
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:
Claims 175 and 205 each recite the broader limitation “cell signaling molecule”, and the claim also recites “growth factor receptor”, “receptor tyrosine kinase receptor”, “neurotransmitter”, “cytokine”, “growth factor”; all of which are considered cell signaling molecules and are therefore narrower statements of the recited “cell signaling molecule”. The claims 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.
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.
Claims 165, 173, 174, and 201 are rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by Raso (U.S. Patent No. 5,501,854).
Independent claim 165 claims a peptide complex comprising a TfR binding peptide and a target-binding peptide that has affinity for the target at a neutral pH, and less affinity at a lower endosomal pH.
Independent claim 201 claims a peptide complex comprising a TfR binding peptide and a target-binding peptide that has affinity for the target.
Raso teaches agents comprising a first portion which delivery the agent to an endosome, and a second agent that binds diphtheria toxin that released the diphtheria toxin within the endosomes at a lower pH (claim 1). Raso teaches this second agent releases the diphtheria toxin at a pH of 4.5-5.5 as compared to a pH of 6.5-7.5 (claims 2 and 3).
Raso further teaches that the first agent is a TfR binding antibody (i.e., “polypeptide”), and the second agent is a pH-sensitive diphtheria toxin antibody (claim 1 and Example 2): “[h]ybrid antibodies were formed with various anti-diphtheria toxin antibodies by linking them to anti-transferrin receptor monoclonal antibodies by a method previously described…”
Therefore, Raso teaches a peptide complex comprising a transferrin binding antibody (i.e., “polypeptide”) and an anti-diphtheria toxin antibody that binds the toxin at a pH of 6.5-7.5 and releases it at the endosomal pH of 4.5-5.5, anticipating the limitations of instant claims 165 and 201.
Regarding instant claim 173, Raso teaches that the anti-diphtheria toxin antibody did not release diphtheria toxin at neutral pH (Col 6, lines 45-46), and the anti-diphtheria toxin released 80% of the toxin at a pH of 5.5 (see Fig. 4), demonstrating that there was a 5-fold decrease in binding between the pH value (i.e., the binding is over 2-fold stronger at neutral pH), anticipating the claimed limitations.
Regarding instant claim 174, Raso teaches that the anti-TfR antibody does not stop binding it target in an endosome with a pH<5 (Fig. 1), anticipating the claimed limitations.
The reference teachings anticipate the claimed invention.
Claims 201, 204, and 217 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Boado et al. (Mol Pharm. 2010 Feb 1;7(1):237-44. doi: 10.1021/mp900235k), as evidenced by Chen et al. (Acta Pharmacol Sin. 2017 Sep;38(9):1205-1235. doi: 10.1038/aps.2017.28).
Boado et al. teaches a polypeptide complex comprising a mouse transferrin receptor targeting antibody complexed with an anti-amyloid ß scFv (Figure 1):
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Thus, Boado et al. teaches a polypeptide complex comprising a TfR binding peptide and a target binding peptide with affinity for Aß, anticipating the limitations of instant claim 201.
Regarding claim 204, Chen et al. is used as an evidentiary reference to demonstrate that the amyloid beta protein is a transmembrane protein, anticipating the claim limitations (Fig. 1):
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Regarding claim 217, Boado et al. teaches that the polypeptide complex is formed by association of the two light chains and two heavy chains, and the CH2/CH3 heavy chain domain associates together to form a bivalent polypeptide complex (Fig 1 and 2):
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Therefore, the polypeptide complex comprises a CH2/CH3 homodimerization domain, anticipating the claim limitations.
The reference teachings anticipate the claimed invention.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 165, 167-174, 201, and 208-212 are rejected under 35 U.S.C. 103 as being unpatentable over Raso (U.S. Patent No. 5,501,854, supra) in view of Crook et al (J Mol Biol. 2020 Jun 26;432(14):3989-4009. doi: 10.1016/j.jmb.2020.04.002).
The teachings of Raso have been discussed in the 35 U.S.C. 102(a)(1)/(2) rejection supra. Raso does not teach a TfR binding peptide comprising a cysteine dense peptide with at least three disulfide bonds (i.e., the limitations of instant claims 167-169, 208, and 209), or the peptide comprising instant SEQ ID NO: 96 (i.e., the limitations of instant claims 170-172 and 210-212).
Crook et al., in the same field of endeavor, teaches that anti-TfR antibodies have some disadvantages due to the immunoglobulin scaffold (pg. 3): “…we have explored alternate protein therapeutic scaffolds in order to bypass some of the liabilities of the immunoglobulin scaffold, including poor tissue permeability [8–10], immunogenicity [11,12], and long serum half-life that can become problematic if toxicities arise…”
Crook et al. further teaches selection of cystine-dense miniproteins that bind to TfR via screening a large combinatorial library for peptide structures that bind to TfR (“Mammalian display screening to identify mature and novel TfR binding CDP” Section). Crook et al. teaches that these CDPs have three disulfide bonds (pg. 5): “[i]t contains three disulfide bonds with a simple hairpin topology…”. Crook et al. teaches multiple identified CDP structures that bind to TfR (Fig. 2):
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Crook et al. teaches potential advantages the CDPs have over antibodies (pg. 3): “…cystine-dense peptides (CDPs) are of particular interest. Their intramolecular disulfide architecture provides particularly high stability metrics [15–17], reducing fragmentation and immunogenicity, while their smaller size could improve tissue penetration and facilitate tunable serum half-life. Their use in drug-like roles throughout every evolutionary clade highlights their utility as drug scaffolds…”
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have modified the invention of Raso in view of Crook et al. to make peptide complexes comprising a pH-sensitive diphtheria antibody to an anti-TfR CDP (i.e., the limitations of instant claims 167-169, 208, and 209) with a reasonable expectation of success, as Crook et al. teaches that these CDPs can be used as such drug scaffolds, and one with ordinary skill in the art would appreciate such anti-TfR CDPs could replace the longer antibody polypeptide in such a complex. One would have been motivated to make this change for the purposes of using the CDPs that have reduced fragmentation and immunogenicity, and increased tissue penetration of the complex, as taught by Crook et al.
Regarding instant claims 170-172 and 210-212, Crook et al. teaches the anti-TfR CDP TfRB1G3 (Fig. 2 supra), which comprises a sequence that is 100% identical to instant SEQ ID NO: 96 (i.e., the elected species of anti-TfR peptide), meeting the claim limitations:
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Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 165, 173, 174, 179, 201, and 206 are rejected under 35 U.S.C. 103 as being unpatentable over Raso (supra) in view of Schröter et al. (MAbs. 2015;7(1):138-51. doi: 10.4161/19420862.2014.985993)
The teachings of Raso have been discussed in the 35 U.S.C. 102(a)(1)/(2) rejection supra. Raso does not teach protein complexes comprising a pH-sensitive anti-diphtheria antibody comprising histidine residues at the target binding interface/CDR regions (i.e., the limitations of instant claims 179 and 216).
Schröter et al., in the same field of endeavor, teaches a genetic approach to generate pH-dependent antibodies that have high affinity at pH 7.4 and a lower affinity at lower pH values such as 6.0 (Abstract). Schröter et al. teaches that this sensitivity allows for the antibody to be recycled, leading to reduction in the need for dosing (Introduction): “…pH-dependent antigen binding allowed dissociation of the antibody-antigen complex in the acidified endosome (pH 6.0) and FcRn-mediated recycling of free antibody….resulted in enhanced antigen clearance that may enable less frequent or lower antibody dosing…”
Schröter et al. teaches a method of generating combinatorial phage display libraries based on an antibody clone with one, two, or three histidine substitutions in the CDR regions, followed by screening of these large libraries to isolate individual variants that have pH sensitivity (“Construction of libraries” and “Isolation of variants with pH-dependent antigen binding” Sections). Schröter et al. further teaches (pg. 147): “[t]his study demonstrates that efficient incorporation of pH-sensitive antigen-binding into antibodies can be performed using combinatorial histidine scanning libraries and YSD. To our knowledge, it is the first time that antibody Fab histidine scanning libraries were screened with YSD that comprehensively considered combinatorial effects of multiple histidine substitutions. Furthermore, the screening strategy described here allows simultaneous screening for both high affinity binding and pH-sensitivity and excludes conventional negative selection steps that are used to select for pH-sensitivity. This strategy could be potentially applied to a variety of antibodies and other protein-based therapeutics and may significantly accelerate the engineering of their pH-sensitive binding functionalities.”
It would have been obvious to one with ordinary skill in the art, before the effective filing date, to have modified the teachings of Rosa in view of Schröter et al. to use the histidine mutagenesis protocol of Schröter et al. to generate anti-diphtheria antibodies that have greater pH sensitivity in the constructs taught by Rosa et al. (i.e., the limitations of instant claims 179 and 216) with a reasonable expectation of success because Schröter et al. teaches such a screening method to generate pH-sensitive antibodies with histidines in the target-binding interface/CDRs. One would have been motivated to make this change for the purposes of increasing antibody recycling in vivo to reduce the number or amount of doses.
The invention encompassed by the instant claims was a prima facie obvious variant of the combined teachings of Boado et al. in view of Crook et al., as evidenced by Chen et al. for the same reasons discussed for Raso in view of Crook et al. supra, especially in absence of evidence to the contrary.
Claims 201, 204, 208-212, and 217 are rejected under 35 U.S.C. 103 as being unpatentable over Boado et al. (Mol Pharm. 2010 Feb 1;7(1):237-44. doi: 10.1021/mp900235k, supra) in view of Crook et al. (supra), as evidenced by Chen et al. (Acta Pharmacol Sin. 2017 Sep;38(9):1205-1235. doi: 10.1038/aps.2017.28, supra).
The teachings of Boado et al. as evidenced by Chen et al. have been discussed in the 35 U.S.C. 102 rejection supra. Boado et al. as evidenced by Chen et al. do not teach a TfR binding peptide comprising a cysteine dense peptide with at least three disulfide bonds (i.e., the limitations of instant claims 208 and 209), or the peptide comprising instant SEQ ID NO: 96 (i.e., the limitations of instant claims 210-212).
The invention encompassed by the instant claims was a prima facie obvious variant of the combined teachings of Boado et al. in view of Crook et al., as evidenced by Chen et al. for the same reasons discussed for Raso in view of Crook et al. supra, especially in absence of evidence to the contrary.
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.
Claims 165, 167-174, 201, and 208-212 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 77-103 of copending Application No. 17/312,703 (App ‘703) in view of Raso (U.S. Patent No. 5,501,854, supra).
App’ 703 claims TfR binding cystine dense peptides (CDPs) comprising SEQ ID NO: 67 (claim 77), further conjugated to an active agent (claim 82). SEQ ID NO: 67 of App ‘703 is 100% identical to instant SEQ ID NO: 96 (i.e., the limitations of instant claims 167-172 and 208-212):
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App ‘703 does not specifically claim the TfR binding CDP complexed with a targeting peptide (i.e., the limitations of instant claim 201), or wherein the targeting peptide has a lower target affinity in the endosomal compartment (i.e., the limitations of instant claim 165).
Raso, in the same field of endeavor teaches agents comprising a first portion which delivery the agent to an endosome, and a second agent that binds diphtheria toxin that released the diphtheria toxin within the endosomes at a lower pH (claim 1). Raso teaches this second agent releases the diphtheria toxin at a pH of 4.5-5.5 as compared to a pH of 6.5-7.5 (claims 2 and 3).
Raso teaches that these protein complexes are useful in delivering diphtheria toxin to cells including T-cell leukemia cells (Example 2), leading to cytotoxicity and cell death (Example 2 and Table 1).
Raso further teaches that the first agent is a TfR binding antibody, and the second agent is a pH-sensitive diphtheria toxin antibody (claim 1 and Example 2): “[h]ybrid antibodies were formed with various anti-diphtheria toxin antibodies by linking them to anti-transferrin receptor monoclonal antibodies by a method previously described…”
Raso teaches a peptide complex comprising a transferrin binding antibody (i.e., “polypeptide”) and an anti-diphtheria toxin antibody that binds the toxin at a pH of 6.5-7.5 and releases it at the endosomal pH of 4.5-5.5 (i.e., the limitations of instant claim 173).
It would have been obvious to one with ordinary skill in the art to have modified the TfR-targeting CDPs claimed by App ‘703 in view of Raso et al. to complex a pH-dependent anti-diphtheria antibody to the TfR CDP claimed by App’703 (i.e., the limitations of instant claims 165, 167-172, 201, and 208-212) with a reasonable expectation of success, as Raso teaches anti-TfR/anti-diphtheria protein complexes that one with ordinary skill would appreciate could incorporate the anti-TfR targeting CDP claimed by App ‘703. One would have been motivated to make this change for the purposes of developing an TfR-targeting diphtheria releasing protein complex to target and kill T-cell leukemia cancer cells, as taught by Raso.
Regarding instant claim 173, Raso teaches that the anti-diphtheria toxin antibody did not release diphtheria toxin at neutral pH (Col 6, lines 45-46), and the anti-diphtheria toxin released 80% of the toxin at a pH of 5.5 (see Fig. 4), demonstrating that there was a 5-fold decrease in binding between the pH value (i.e., the binding is over 2-fold stronger at neutral pH), anticipating the claimed limitations.
Regarding instant claim 174, Raso teaches that the anti-TfR antibody does not stop binding it target in an endosome with a pH<5 (Fig. 1), anticipating the claimed limitations.
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘703 in view of Raso. This is a provisional nonstatutory double patenting rejection.
Claims 179 and 216 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 77-103 of copending Application No. 17/312,703 (App ‘703, supra) in view of Raso (supra), as applied to claims 165, 167-174, 201, and 208-212 above, and further in view of Schröter et al. (MAbs. 2015;7(1):138-51. doi: 10.4161/19420862.2014.985993, supra)
The teachings of App ‘703 in view of Raso have been discussed supra. The combined teachings do not teach protein complexes comprising a pH-sensitive anti-diphtheria antibody comprising histidine residues at the target binding interface/CDR regions (i.e., the limitations of instant claims 179 and 216).
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘703 in view of Raso, and further in view of Schröter for the same reasons discussed in the 35 U.S.C. § 103 rejection supra. This is a provisional double patenting rejection.
Conclusion
No claim is allowed.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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