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 11/27/2023, is acknowledged.
Claims 3-5, 7, 9-13, 16, 17, 23-29, 32-40, 45, 47, 54-59, 61-70, 72-75, and 78-86 are cancelled.
Claims 1, 2, 6, 8, 14, 15, 18-22, 30, 31, 41-44, 46, 48-53, 60, 71, 76, and 77 are currently pending.
Claim 1 is an independent claim.
Election/Restrictions
Applicants’ election without traverse of Group I, claims 1, 2, 6, 8, 14, 15, 18-22, 30, 31, 41-44, 46, and 51-53, directed to a NPC1 binding polypeptide comprising a FN3 domain with a modified FG, BC, and/or DE loops, and the Species of: i) the FN3 domain designated as N23, which has the sequence of SEQ ID NO: 36, and comprises FG, BC, CD, and DE loops of SEQ ID NO: 6, 19, 23, and 31, respectively; ii) a pharmaceutically active moiety conjugate; and iii) a cancer therapeutic, filed on 6/03/2026, is acknowledged.
As stated in the Restriction Requirement mailed on 6/03/2026, Group I (claims 1, 2, 6, 8, 14, 15, 18-22, 30, 31, 41-44, 46, and 51-53) and III (claims 60, 71, 76, and 77) have unity of invention. Please note that the product of Group II is not eligible for rejoinder.
Claims 41, 42, 44, and 46 read on unelected species of conjugated moieties.
Claims 41, 42, 44, 46, and 48-50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions and/or species.
Claims 1, 2, 6, 8, 14, 15, 18-22, 30, 31, 43, 51-53, 60, 71, 76, and 77 are under examination as reading on the NPC1 binding FN3 domain elected clone species N23 and a pharmaceutically active cancer therapeutic conjugated moiety.
The elected species of monobody sequence recited in claim 18 is free of the prior art. The search and examination has been extended to the other species in this claim.
Priority
Applicant’s claim for the benefit of a prior-filed U.S. Provisional Patent Application
Serial No. 63/112,031, filed November 10, 2020, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 5/09/2023, 7/27/2023, 10/09/2024, and 12/24/2025 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.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Specifically, amino acid sequences are disclosed in ¶[0066] (“…(Gly3-Ser)n…(Gly4-Ser)3…”) and ¶[0069] (“…His6…”).
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 disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically, the specification discloses embedded hyperlinks in ¶[0147]. 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.
The use of the terms:
SYTO™ (¶[0018], [0025]);
PROTAC® (¶[0073], [0074], [0150]);
KEYTRUDA® (¶[0133]);
OPDIVO® (¶[0133]);
LIBTAYO® (¶[0133]);
BAVENCIO® (¶[0133]);
IMFINZI® (¶[0133]);
YERVOY® (¶[0133]);
RILUTEK® (¶[0152]);
Radicava® (¶[0152]);
Mirapex® (¶[0153]);
REQUIP® (¶[0153]);
NEUPRO® (¶[0153]);
Apokyn® (¶[0153]);
Zelapar® (¶[0153]);
Azilect® (¶[0153]);
Xadago® (¶[0153]);
Comtan® (¶[0153]);
Ongentys® (¶[0153]);
Tasmar® (¶[0153]);
Cogentin® (¶[0153]);
XENAZINE® (¶[0154]);
AUSTEDO® (¶[0154]);
Haldol® (¶[0154]);
Risperdal® (¶[0154]);
Zyprexa® (¶[0154]);
Seroquel® (¶[0154]);
Gocovri ER® (¶[0154]);
Osmolex ER® (¶[0154]);
Keppra® (¶[0154]);
Elepsia XR® (¶[0154]);
SPRITAM® (¶[0154]);
Klonopin® (¶[0154]);
Namenda™ (¶[0155]);
Aricept® (¶[0155]);
RAZADYNE® (¶[0155]);
Exelon® (¶[0155]);
Aduhelm™ (¶[0155]);
Advil® (¶[0157]);
Mortin® (¶[0157]);
Aleve® (¶[0157]);
Trexall® (¶[0157]);
Otrexup® (¶[0157]);
Arava® (¶[0157]);
Plaquenil® (¶[0157]);
Azulfidine® (¶[0157]);
Orencia® (¶[0157]);
Humira® (¶[0157]);
Kineret® (¶[0157]);
Cimzia® (¶[0157]);
Enbrel® (¶[0157]);
Simponi® (¶[0157]);
Remicade® (¶[0157]);
Rituxan® (¶[0157]);
Kevzara® (¶[0157]);
Actemra® (¶[0157]);
Olumiant® (¶[0157]);
Xeljanz® (¶[0157]);
Rinvoq® (¶[0157]);
Zetia® (¶[0158]);
Binosto® (¶[0160], [0161]);
Fosamax® (¶[0160]);
Boniva® (¶[0160], [0161]);
Actonel® (¶[0160], [0161]);
Atelvia® (¶[0160], [0161]);
Reclast® (¶[0160], [0161]);
Zometa® (¶[0160], [0161]); and
Aredia® (¶[0161]);
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.
Claim Objections
Claim 18 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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 1, 2, 6, 8, 14, 15, 19-22, 30, 31, 43, 51-53, 60, 71, 76, and 77 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.
Claim 1, 6, 8, 19-22, 30, 31, 51-53, 60, 71, 76, and 77 encompass FN3 domains or methods of using FN3 domains with modified FG, BC, CD, and/or DE loops, or a combination thereof, with no recited structure and the function of “NPC1 binding polypeptide”. This encompasses a broad genus of millions to billions of different polypeptide structures, defined by their amino acid sequences, with this recited function.
Claim 2 encompasses a broad genus of FN3 domains with any combination of the recited modified FG, BC, CD, and/or DE loop sequences recited in the claims, results in a large genus of thousands of different structures with the recited function of “NPC1 binding polypeptide”.
Claim 15 encompasses a broad genus of FN3 domains with the recited sequences with up to 20% variation, which results in a genus of millions to billions of polypeptide structures with the function of “NPC1 binding polypeptide”. For example, the elected species of SEQ ID NO: 36 is 36 residues in length, allowing for (36*0.2) = 7 mutations. 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 36 residues in length with 7 allowed substitutions, there would be
36
!
*
19
(
7
)
36
-
7
!
7
!
Which is approximately 2.8x1016 polypeptide structures with the recited function of “NPC1 binding polypeptide”.
However, the specification fails to provide adequate written description support for a genus of polypeptide structures with a partial structure at best and the function of “NPC1 binding polypeptide”.
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 generation of monobodies that specifically bind to NPC1 (Examples 1 and 2). The monobodies are a conserved fibronectin type-III backbone structure with connecting loops that can be modified to specifically bind to targets, which is comparable to antibody CDRs (¶[0036]-[0037]): “…NPCI binding polypeptide comprises a fibronectin type III (FN3) domain having a modified FG loop amino acid sequence, a modified BC loop amino acid sequence, a modified CD loop amino acid sequence, a modified DE loop amino acid sequence…[t]he FN3 domain is an evolutionary conserved protein domain that is about 100 amino acids in length and possesses a beta sandwich structure…[t]hree of the six loops, i.e., loops DE, BC, and FG, correspond topologically to the complementarity determining regions of an antibody, i.e., CDR1, CDR2, and CDR3. The remaining three loops are surface exposed in a manner similar to antibody CDR3…one or more of the loop regions of each FN3 domain of the binding molecule are modified to enable specific binding to NPC1.”
The specification further discloses screening of large monobody libraries to identify specific monobody structures that bind to NPC1 (¶[0171]): “…screening of two proprietary monobody libraries produced the NPC1 monobodies described herein, i.e., binding molecules having an amino acid sequence of any one of SEQ ID NOs: 32-43) that showed strong target binding…”
The specification discloses identification of 12 specific monobody clones that bind to NPC1 from the screening of libraries (Table 1), which are NPC1N-N8, N16, N18, N22, N23, N24, N26, N31, N34, N35, N38, and NPC1C-C45.
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.).
The claims are directed to a genus of monobody structures with a partial structure at best and the function of “NPC1 binding polypeptide”, while the instant specification only discloses 12 different NPC1 binding polypeptide structures, all of which are monobodies. The monobodies are specific FN3 backbone structures with BD, CD, DE, and FG loop sequences that give rise to the function of “NPC1 binding polypeptide”. These 12 different monobody constructs with different loop sequences do not sufficiently represent the broadly claimed genera of monobodies with a partial structure at best encompassed by the claims.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed binding polypeptides 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 class of binding polypeptides, and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed class of binding polypeptides that bind to NPC1, 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.
The specification at best describes plan for making additional monobody structures that have the recited function of “NPC1 binding polypeptide”, and then identifying those that satisfy the claim limitations, but a mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011).
The specification discloses only 12 engineered FN3 based monobody structures, defined by their amino acid sequences (SEQ ID NO: 32-43) within the claimed scope. It is unlikely that other monobodies as defined by the claims which contain less than the BC, CD, DE, and FG sequences of the anti-NPC1 monobodies NPC1N-N8, N16, N18, N22, N23, N24, N26, N31, N34, N35, N38, and NPC1C-C45, incorporated into the FN3 domain backbone have the required binding function to NPC1. The specification provides no direction or guidance regarding how to produce additional monobody structures with the function of “NPC1 binding polypeptide” as broadly defined by the claims. which may contain less than the full complement of FN3 modified loops, fused to the FN3 backbone, have the required binding function. The specification provides no direction or guidance regarding how to produce monobody constructs with the function of “NPC1 binding polypeptide” as broadly defined by the claims.
Additionally, the current state of the art also teaches that FN3-based monobodies have defined loop region sequences that give rise to specific binding. Koide et al. (J Mol Biol. 1998 Dec 11;284(4):1141-51. doi: 10.1006/jmbi.1998.2238. PMID: 9837732) teaches that the FN3 domain can be used as a scaffold to randomize the surface-exposed loops of the polypeptide to screen for binders to different targets, in the same way that antibody CDR regions are varied to discover novel antibodies that bind to a specific antigen (Introduction): “…we report the isolation of novel binding proteins using a scaffold consisting of the fibronectin type III domain… have built our system on the tenth FN3 unit of human fibronectin (referred to simply as FN3 hereinafter). FN3 is small (94 residues) and monomeric. It is one of the few members of the immunoglobulin superfamily that do not have disulfide bonds, and overexpression of correctly folded FN3 in Escherichia coli is straightforward…introduce a large number of mutations to the FN3 framework without drastically altering its structure and stability, and (2) use phage display to select among these FN3 mutants for those with novel binding functions…”
Furthermore, Hantschel et al. (Curr Opin Struct Biol. 2020 Feb;60:167-174. doi: 10.1016/j.sbi.2020.01.015) teaches that monobodies are developed from combinatorial libraries of modified/mutated loops in a constant scaffold, which are screened for specific binding to targets, much like the way new antibody structures are developed (pg. 167): “…monobodies are developed from two types of combinatorial phage-display libraries with different diversification patterns…one concentrates diversity in three loops that are structurally equivalent to antibody CDRs; the other uses two loops on opposite ends of the FN3 scaffold and the b-sheet surface in between…”
Both the instant specification discloses, and the prior art teaches, that much like antibodies, development of new monobody structures that bind to a specific target protein is unpredictable, and requires new monobody structures to be discovered through screening large libraries of mutated monobody structures to identify novel binding structures. Neither the instant specification nor the prior art provides sufficient direction on how to produce monobodies with the function of “NPC1 binding polypeptide” as broadly defined by the claims.
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 anti-TMPRSS6 antibodies or antigen binding fragments thereof 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 1, 2, 6, 8, 15, 19-22, 30, 31, 43, 51-53, 60, 71, 76, and 77 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 for these claims, it is recommended to amend claim 1 to recite the specific monobody structures, defined by their amino acid sequences, of the NPC structures NPC1N-N8, N16, N18, N22, N23, N24, N26, N31, N34, N35, N38, and NPC1C-C45, with the function of “NPC1 binding polypeptide”.
Regarding claim 14, the claim uses open language “comprising” and, for example, “a modified FG loop amino acid sequence of SEQ ID NO…”. The open language “comprising” and “a modified…” are also used for the BC, CD, and DE loops. The phrases results in monobodies comprising the claimed loop sequences or any portion of the claimed sequences. The claim terminology of, for example, “a modified FG loop amino acid sequence of SEQ ID NO…” does not place size limits on the claimed loop sequences, but rather reads on any portion of the claimed loop sequences. The loop sequences are generic with respect to size, encompassing anything from dimers on up to the full size of the claimed SEQ ID NOs.
To resolve this issue for claim 14, it is recommended to amend the claim to recite “…the modified FG loop amino acid sequence…”, as well as for the other claimed loop sequences, placing size limitations on all of the claimed monobody loop sequences.
Claims 60, 71, 76, and 77 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
Breadth of claims and nature of invention:
Claim 60 encompasses method of treating any and all cancers, regardless of NPC1 expression status, comprising administration of NPC1 binding polypeptides.
Claim 71 encompasses methods of treating any and all infectious diseases in a subject comprising administration of NPC1 binding polypeptides.
Claims 76 and 77 encompasses methods of enhancing endosomal release of a pharmaceutically active moiety in a subject comprising administration of NPC1 binding polypeptides that are either conjugated to a pharmaceutically active moiety (claim 76), or in combination with a pharmaceutically active moiety.
Amount of direction and existence of working examples:
The instant specification discloses that NPC1 is expressed in some mutant KRas tumors (Example 1): “…NPC I has a necessary role in cholesterol trafficking in a mutant KRas cancer cell lines…” Also see Fig. 1B:
PNG
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633
611
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The instant specification discloses screening of combinatorial libraries to identify monobody structures that bind to NPC1 (¶[0171]): “…screening of two proprietary monobody libraries produced the NPC1 monobodies described herein, i.e., binding molecules having an amino acid sequence of any one of SEQ ID NOs: 32-43) that showed strong target binding at 2.5nM…”
The instant specification further discloses that NPC1 expressing and mutant KRas expressing colorectal cell lines uptook the monobodies via micropinocytosis (¶[0174]): “…N34 shows a dose-dependent accumulation of the LC3B in HCT-116 but not HCA7 cells…suggesting a dependence on micropinocytosis for NPC1 inhibition by NPC1-targeting monobodies…”
The instant specification additionally discloses that in mouse xenograft models of mutant KRas expressing DLD-1 cells, intratumoral injection of a monobody N34 led to labeling of tumor cells, accumulation of the autophagy marker LC3B, and cholesterol accumulation (Fig. 11 and 12), as well as increases in ERK phosphorylation (Fig. 13B), however the instant specification does not disclose that these tumors were treated (i.e., there is a reduction or reversal of tumor growth).
The instant specification further discloses that in vitro, co administration of an NPC1 monobody with a domain of GFP (Fig. 16), calcein (Fig. 17), or nanoparticles (Fig. 18) led to accumulation of these domains inside cells. However, there is significant variation as to the potency of the monobody. For example, The N34 monobody did not increase intracellular uptake of a 90nm nanoparticle when compared to incubation of the cells with the nanoparticle alone:
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658
421
media_image2.png
Greyscale
Additionally, the instant specification does not disclose a working examples of a method of treating a tumor, a disease, or allowing endosomal release of a pharmaceutically active moiety in a subject comprising administration of the active moiety and a NPC1 monobody.
Level of predictability, state of prior art, and quantity of experimentation needed:
There are no disclosed working examples of treating cancer, treating an infectious disease, or enhancing endosomal reseals of a pharmaceutically active moiety in a subject comprising administration of an NPC1 polypeptide coupled to any pharmaceutically active moiety or in combination with the moiety (i.e., the limitations of instant claim 60, 70, 76, and 77).
The instant specification discloses that even in vitro different anti-NPC1 monobodies will have different effects on cells, for example in increasing endosomal release of 90nm nanoparticles.
Additionally, the prior art teaches that there is significant unpredictability in using the claimed methods. Yu et al. (Clin Chim Acta. 2014 Feb 15;429:69-75. doi: 10.1016/j.cca.2013.11.026) teaches that NPC1 is a membrane protein expressed in virtually all cells, as it plays a key role in modulating cellular cholesterol levels, and is localized to the endosomal and lysosomal subcellular compartments (“Introduction): “[m]embrane fluidity of all cells is tightly regulated by the ordered packing of cholesterol between phospholipid molecules…NPC1 is a transmembrane glycoprotein located in the limiting membrane of late endosome/lysosome (LE/LY). It can transfer low-density lipoprotein (LDL)-cholesterol (LDL-C) from LE/LY to endoplasmic reticulum (ER) for esterification or to plasma membrane for efflux, a crucial process governing the balance between macrophage cholesterol import and export…”
Additionally, Lim et al. (Immunol Cell Biol. 2011 Nov;89(8):836-43. doi: 10.1038/icb.2011.20) teaches that micropinocytosis is a regulated nonselective form of endocytosis (Abstract): “[m]acropinocytosis is a regulated form of endocytosis that mediates the non-selective uptake of solute molecules…” Lim et al. further teaches that normal cells undergo this process either constitutively or in response to growth factor stimulation (“Macropinocytosis” Section): “[m]acropinocytosis is a signal-dependent process that normally occurs in response to growth factor stimulation, such as macrophage colony-stimulating factor-1 (CSF-1), epidermal growth factor (EGF) and platelet-derived growth factor or tumour-promoting factor, such as phorbol myristate acetate. However, some specialised cell types such as antigen-presenting cells are capable of constitutive micropinocytosis…”
The prior art teaches: 1) NPC1 is expressed by many cells and not localized to the plasma membrane, but in late endosomes and lysosomes; and 2) normal cells undergo macropinocytosis, either constitutively or in response to growth factor stimulation. In view of this and the lack of working examples of the claimed methods, there is significant unpredictability in whether or not administration of NPC1 monobodies coupled to a pharmaceutically active moiety or in combination with the moiety would reach their intended target (i.e., tumors), and in a large enough level to have an effect. Furthermore, there is even greater unpredictability in light of the specification disclosure that different NPC-1 monobodies have different effects in cells (see supra).
The specification does not reasonably provide enablement to make and use the invention of instant claims 60, 71, 76, and 77.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
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 21 and 53 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.
The recitation "derivative” in claims 21 and 53 is indefinite because it is unclear what changes or how many changes could have occurred to result in a derivative. Derivation only describes the source and not the result. To resolve this issue, it is recommended to amend the claims to delete the “derivative” language.
Additionally, claims 21 and 53 contains the trademark/trade name PROTAC®. 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 a proteolysis targeting chimera and, accordingly, the identification/description is indefinite. It is recommended to amend the claims to remove the trademark to resolve this issue.
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 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Patel et al. (Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1657-62. doi: 10.1073/pnas.96.4.1657) in view of Hackel et al. (Protein Eng Des Sel. 2010 Apr;23(4):211-9. doi: 10.1093/protein/gzp083. Epub 2010 Jan 12).
Claim 1 recites a NPC-1 binding polypeptide comprising at least one modified FG, BC, CD, and/or DE loops that enable it to bind to NPC-1.
Patel et al. teaches use of anti-NPC1 antibodies in assays to determine the localization of NPC1 in tissues such as brain tissue (Abstract): “…using a specific antipeptide antibody to human NPC1, we have here investigated the cellular and subcellular localization and regulation of NPC1. By light and electron microscopic immunocytochemistry of monkey brain, NPC1 was expressed predominantly in perisynaptic astrocytic glial processes.”
Patel et al. does not teach anti-NPC monobodies comprising a FN3 domain with at least one modified FG, BC, CD, and/or DE loops (i.e., the limitations of instant claim 1).
Hackel et al., in the same field of endeavor, teaches a combinatorial library of the 10th type III FN3 domain (Abstract): “…we directly compare minimal and maximal amino acid diversity libraries in the context of the 10th type III domain of human fibronectin.” Hackel et al. teaches methods of using the combinatorial library to screen for novel monobody binders to a selected target (“Binder engineering”). Hackel et al. teaches that the identified monobodies can be useful in both affinity purification and as a detection reagent (Introduction, pg. 214-215): “…we sought to develop useful reagents with advantageous biophysical properties. High-yield bacterial expression enables inexpensive production of Fn3 domains. The absence of lysines near the engineered binding surface and the cysteine-free sequence permits both amine- and thiol-based conjugation chemistries for immobilization or fluorophore coupling. The small, single-domain architecture facilitates multifunctional protein fusions. Engineered Fn3 domains have demonstrated utility as detection agents.”
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 teachings of Patel et al. in view of Hackel et a. to use the combinatorial library of Hackel et al. to develop novel NPC-1 monobody binders (i.e., the limitations of instant claim 1) with a reasonable expectation of success, as Hackel et al. teaches a method of screening for target monobody binders using the combinatorial library. One would have been motivated to make this change for the purposes of make useful detection reagents that bind to NPC1 to, for example, examine subcellular localization of NPC1 in brain tissue.
Regarding claim 3, Hackel et al. teaches the monobodies are based on the 10th domain of human FN3 (see supra), meeting the claim limitations.
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.
Conclusion
No claims is allowed.
The elected species of NPC-1 binding monobody structure, N23, is neither taught or suggested by the prior art.
Claim 18 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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