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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 2, 11, 16, 17, 19, 21, 24, 32, 49-50, in the reply filed on 12/20/2025 is acknowledged.
Applicant’s election of the species SEQ ID NO: 6, 38, and 39 in the reply filed on 12/20/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon further search and examination, peptides with 90% or greater sequence identity to SEQ ID NO: 6, wherein the optional residues are omitted, including 100% sequence identity to SEQ ID NO: 6, were found to be free of the art. The closest prior art is US20190155988A2 (published 5/23/2019, effectively filed 11/16/2016), which teaches SEQ ID NO: 25 that exhibits 46.9% sequence identity to the instant SEQ ID NO: 6.
Accordingly, the species election was expanded to include SEQ ID NO: 1-5 and 7-9, wherein the optional residues are omitted, all of which were also found to be free of the art. The closest prior art is as follows:
SEQ ID NO: 28 of US20190155988A2 exhibits 46.3% identity to SEQ ID NO: 1
SEQ ID NO: 28 of US20190155988A2 exhibits 46.8% identity to SEQ ID NO: 2
SEQ ID NO: 28 of US20190155988A2 exhibits 44.3% identity to SEQ ID NO: 3
SEQ ID NO: 25 of US20190155988A2 exhibits 47.7% identity to SEQ ID NO: 4
SEQ ID NO: 25 of US20190155988A2 exhibits 48.7% identity to SEQ ID NO: 5
SEQ ID NO: 123 of US20230142283A1 (effectively filed 3/5/2020) exhibits 46.7% identity to SEQ ID NO: 7
SEQ ID NO: 568 of US20190012428A1 (effectively filed 12/16/2015) exhibits 40.2% identity to SEQ ID NO: 8
SEQ ID NO: 554 of US20190012428A1 exhibits 39.4% identity to SEQ ID NO: 9
Additionally, antibody species comprising peptides with at least 90% identity to SEQ ID NO: 38 and 39 are known in the art but it is not obvious to combine them in a particle comprising a plurality of polymers wherein each monomer in the polymer comprises a sequence with at least 90% identity to one of SEQ ID NO: 1-9 because such peptides are novel and non-obvious in the art, as stated above. The closest prior art is US20190192691A1, which teaches SEQ ID NO: 204986, which exhibits 99.2% identity to SEQ ID NO: 38, and SEQ ID NO: 204987, which exhibits 99.1% sequence identity to SEQ ID NO: 39.
Likewise, it is also not obvious to combine antibody species comprising peptides with at least 90% identity to any of SEQ ID NO: 11-37 and 40-56 for the same reasoning above. The closest art is as follows:
SEQ ID NO: 49 of US20220275100A1 (effectively filed 9/11/2018) exhibits 95.8% identity to SEQ ID NO: 11
SEQ ID NO: 53 of US20090280128A1 (effectively filed 12/20/2005) exhibits 97.8% identity to SEQ ID NO: 12
SEQ ID NO: 9 of US20180072803A1 (effectively filed 4/20/2017) exhibits 95.3% identity to SEQ ID NO: 13
SEQ ID NO: 5 of US20150139982A1 (effectively filed 7/19/2012) exhibits 97.8% identity to SEQ ID NO: 14
SEQ ID NO: 21 of US20180251561A1 (effectively filed 10/7/2015) exhibits 95.9% identity to SEQ ID NO: 15
SEQ ID NO: 29 of US20120039916A1 (effectively filed 8/13/2010) exhibits 94.3% identity to SEQ ID NO: 16
SEQ ID NO: 5 of US20180318392A1 (effectively filed 5/3/2018) exhibits 90.2% identity to SEQ ID NO: 17
SEQ ID NO: 14 of US20130209492A1 (effectively filed 8/19/2011) exhibits 90.7% identity to SEQ ID NO: 18
SEQ ID NO: 268 of US20180340030A1 (effectively filed 4/4/2017) exhibits 99.8% identity to SEQ ID NO: 19
SEQ ID NO: 49 of US20140221622A1 (effectively filed 12/28/2012) exhibits 100% identity to SEQ ID NO: 20
SEQ ID NO: 46 of US20170158772A1 (effectively filed 12/7/2015) exhibits 99.7% identity to SEQ ID NO: 21
SEQ ID NO: 50 of US20170158772A1 (effectively filed 12/7/2015) exhibits 100% identity to SEQ ID NO: 22
SEQ ID NO: 123 of US20120301400A1 (effectively filed 10/8/2010) exhibits 100% identity to SEQ ID NO: 23
SEQ ID NO: 69 of US20200048345A1 (effectively filed 6/23/2012) exhibits 100% identity to SEQ ID NO: 24
SEQ ID NO: 44 of US20120237498A1 (effectively filed 9/9/2010) exhibits 100% identity to SEQ ID NO: 25
SEQ ID NO: 46 of US20120237498A1 (effectively filed 9/9/2010) exhibits 100% identity to SEQ ID NO: 26
SEQ ID NO: 51 of US20060088523A1 (effectively filed 10/20/2004) exhibits 100% identity to SEQ ID NO: 27
SEQ ID NO: 52 of US20060088523A1 (effectively filed 10/20/2004) exhibits 100% identity to SEQ ID NO: 28
SEQ ID NO: 19 of US20150337027A1 (effectively filed 4/23/2014) exhibits 100% identity to SEQ ID NO: 29
SEQ ID NO: 33 of US20190194350A1 (effectively filed 2/20/2016) exhibits 81.4% identity to SEQ ID NO: 30
SEQ ID NO: 1545 of US20200291120A1 (effectively filed 2/11/2019) exhibits 95.5% identity to SEQ ID NO: 31
SEQ ID NO: 1 of US20120141373A1 (effectively filed 5/7/2009) exhibits 94.2% identity to SEQ ID NO: 32
SEQ ID NO: 603 of US20220411504A1 (effectively filed 5/27/2020) exhibits 82.4% identity to SEQ ID NO: 33
SEQ ID NO: 536 of US20220411504A1 (effectively filed 5/27/2020) exhibits 97% identity to SEQ ID NO: 34
SEQ ID NO: 5328 of US20210292393A1 (effectively 3/9/2020) exhibits 95.8% identity to SEQ ID NO: 35
SEQ ID NO: 12 of US20190185570A1 (effectively filed 9/30/2015) exhibits 99.8% identity SEQ ID NO: 36
SEQ ID NO: 54 of US20060088523A1 (effectively filed 10/20/2004) exhibits 100% identity to SEQ ID NO: 37
SEQ ID NO: 19 of US20150259425A1 (effectively filed 10/1/2013) exhibits 100% identity to SEQ ID NO: 40
SEQ ID NO: 20 of US20150259425A1 (effectively filed 10/1/2013) exhibits 100% identity to SEQ ID NO: 41
SEQ ID NO: 19 of US20090181015A1 (effectively filed 5/26/2005) exhibits 100% identity to SEQ ID NO: 42
SEQ ID NO: 22 of US20090181015A1 (effectively filed 5/26/2005) exhibits 100% identity to SEQ ID NO: 43
SEQ ID NO: 2 of US20070110754A1 (effectively filed 11/04/2003) exhibits 100% identity to SEQ ID NO: 44
SEQ ID NO: 4 of US20070110754A1 (effectively filed 11/04/2003) exhibits 100% identity to SEQ ID NO: 45
SEQ ID NO: 5 of US20070110754A1 (effectively filed 11/04/2003) exhibits 100% identity to SEQ ID NO: 46
SEQ ID NO: 5 of US20180318392A1 (effectively filed 5/3/2018) exhibits 97.4% identity to SEQ ID NO: 47
SEQ ID NO: 420 of US20150064204A1 (effectively filed 8/30/2013) exhibits 99.8% identity to SEQ ID NO: 48
SEQ ID NO: 378 of US20150064204A1 (effectively filed 8/30/2013) exhibits 100% identity to SEQ ID NO: 49
SEQ ID NO: 23 of US20070098719A1 (effectively filed 3/25/2005) exhibits 99.8% identity to SEQ ID NO: 50
SEQ ID NO: 22 of US20070098719A1 (effectively filed 3/25/2005) exhibits 100% identity to SEQ ID NO: 51
SEQ ID NO: 198 of US20110256154A1 (effectively filed 4/9/2010) exhibits 96.8% identity to SEQ ID NO: 52
SEQ ID NO: 328 of US20210107981A1 (effectively filed 11/11/2014) exhibits 97.4% identity to SEQ ID NO: 53
SEQ ID NO: 23 of US20070098719A1 (effectively filed 3/25/2005) exhibits 99.8% identity to SEQ ID NO: 54
SEQ ID NO: 22 of US20070098719A1 (effectively filed 3/25/2005) exhibits 100% identity to SEQ ID NO: 55
SEQ ID NO: 27 of US20180244752A1 (effectively filed 4/19/2018) exhibits 100% identity to SEQ ID NO: 56
Although the species are free of the art, other objections and rejections have been raised below that prevent any claim from being allowable.
Claim Status
Claims 1, 2, 11, 16-17, 19, 21, 24, 32, 49-50, and 63-76 are pending. Claims 1, 2, 16-17, 19, 32, and 49-50 are currently amended. Claims 63-76 are new.
Priority
The instant application is the 371 national stage entry of PCT/US2021/036117, filed 6/7/2021, which claims priority to the provisional applications 63/088,576, filed 10/7/2020, 63/088,586, filed 10/7/2020, 63/085,351, filed 9/30/2020, and 63/036,062, filed 6/8/2020. The priority date of 6/8/2020 is acknowledged.
Information Disclosure Statement
The IDS’s filed on 5/17/2023 (two filed this day), 11/222/2024 (two filed this day), 9/2/2025, and 9/3/2025 are under consideration. Any strikethrough is owed to lack of a copy of the document in the file wrapper.
Drawings
The drawings are objected for the following reasons:
Figure 1 – All of the text in the figure is too small and blurry to read.
Figure 2 – The text that occurs below “A” – “E” as well as the text that occurs above the arrows and “2x design” or “2x” (see example below, where text is boxed) is too small and blurry to read:
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296
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Additionally, EM pictures and insets are uninterpretable, see below as an example
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382
186
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Figure 4 – The text is too small and blurry to read.
Figure 4B – It is difficult to determine which line/shape in the graph corresponds with which line/shape in the legend because the figure is in grayscale.
Figure 5A – The color of the text shown below makes it difficult to read:
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Figure 6B – The graphs are too small and the text too small and blurry to read.
Figure 7 – The text is too small and blurry to read.
Figure 7A – It is difficult to determine which line/shape in the graph corresponds with which line/shape in the legend because the figure is in grayscale.
Figure 8C – The text is too small and blurry to read.
Figure 8D – The images are uninterpretable.
Figure 8E – The text on the y-axis is too small and blurry to read.
The remaining figures are acceptable but could be made easier to read by improving the font size and/or color.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
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 incorporation-by-reference paragraph, 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.
Specifically, the file size needs to be listed in bytes, not KB.
Specification
The Specification makes reference to supplementary materials (see Pg 56, line 4, and Pg 57, line 2). It is assumed these supplementary materials include the other documents with the “spec” document codes entitled “Appendix 1” and a document that has “Ticket Information View” on the first page.
The disclosure is objected to because of the following informalities:
Pg 56, line 5 refers to Figure 61a but there is no Figure 61a.
Appropriate correction is required.
Claim Objections
Claim 11 is objected to because of the following informalities:
Line 1 of the claim recites “(i) residues…” but then does not recite (ii) or any other additional numbers. Either remove “(i)” or add in “(ii), (iii), etc” to improve the clarity of the claim.
Line 3 of the claim recites “present at an Fc binding, interface”. Remove the comma between “binding” and “interface” such that the claim reads “present at an Fc binding interface”.
Claim 19 is objected to because of the following informalities: the last line recites “90% identical to the ammo acid sequence of SEQ ID NO: 5” (emphasis added).
Appropriate correction is required.
Claim Interpretation
Claim 1 recites “… a plurality of polypeptide polymers, wherein each monomer in the polymers comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 1-9…” (emphasis added). This claim is being interpreted as any peptide with 90% or more sequence identity to any one of SEQ ID NO: 1-9 across the entire length of the peptide, including a peptide or protein encompassing or containing a sequence with at least 90% identity to one of SEQ ID NO: 1-9, meets the limitation of the claim. Conversely, smaller fragments encompassed by SEQ ID NO: 1-9 (i.e., dipeptides) are being interpreted as not meeting the limitations of the claim.
This same interpretation is being applied to all other instances wherein “an amino acid” is recited in the claims (claims 16, 19, 32, 50, 63-72, and 74-76).
Claim 1 further recites that each of the above polymers “is non-covalently bound to one Fc domain” in addition to limitations regarding the antibodies, wherein the α-Tie2, α-TNFRSF and Ang F domain dimers “is non-covalently bound via the first Fc domain to one polypeptide monomer chain of a first polymer and non-covalently bound via the second Fc domain to one polypeptide monomer of a second polymer”. These limitations describe functional rather than a structural elements of the instant invention. As such, the claim is being interpreted based upon the structural limitations (a peptide with at least 90% sequence identity to SEQ ID NO: 1-9; α-Tie2 antibodies, α-TNFRSF antibodies, and Ang F domain dimers, each of which comprise a first and second Fc domain), where the functional limitations are properties endowed by the structures. Additionally, the limitation “the particle comprises dihedral, tetrahedral, octahedral, or icosahedral symmetry” is being interpreted similarly, wherein the symmetry of the particle is derived from and endowed by the aforementioned structural elements of claim 1.
The same interpretation is being applied to all other instances wherein functional language is recited in the claims (e.g., claims 32 and 49).
Claim 2 recites the polymer comprises monomers with some amino acid differences and/or (i) the particle comprises polymers that are not homo-oligomers or (ii) each polymer in the particle is identical and each polymer is a homo-polymer. The claim is being interpreted as having the first limitation (the polymer comprises monomers with some amino acid differences) and (i) or (ii); or (i) or (ii).
Claim Rejections - 35 USC § 112
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 11, 19, and 50 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.
Claim 11 recites the limitation “residues… as defined in Table 2” and/or “residues… as defined in Table 3” and/or residues… as defined in Table 4”. The claim is indefinite because tables can be readily incorporated into the claim and reference to the specification is improper. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant's convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)." MPEP 2173.05(s).
Claim 11 further recites in lines 5 and 7 that substitutions relative to the reference sequence of any one of SEQ ID NO: 1-9 comprise, consist essentially of, or consist of substitutions at polar residues (emphasis added). These limitations make the scope of the claim indefinite as it is unclear whether the substitutions comprise/consist essentially of polar residues (meaning, are open to additional mutations beyond those at polar residues) or consist of polar residues (meaning, are limited to only polar residues). For purposes of examination, the limitations are being interpreted as substitutions comprising or essentially consisting of polar residues.
Claim 11 further recites narrow and broad limitations regarding the types of polar substitutions; in lines 5-6, the substitution comprises substitutions at polar residues in the reference polypeptide, but in lines 7-8, the substitution comprises substitutions at polar residues at non-Gly/Pro residues in loop positions. These limitations make the scope of the claim indefinite as it is unclear whether the substitutions can include polar residues anywhere in the reference sequence or are limited to occurring at only non-Gly/Pro residues in loop positions. For purposes of examination, the limitations are being interpreted as substitutions at polar residues anywhere in the reference sequence.
Claim 19 recites the limitation "the plurality of homo-polymers" in lines 1 and 4-5. There is insufficient antecedent basis for this limitation in the claim as there is only a prior recitation of a plurality of polypeptide polymers but no recitation of a plurality of homo-polymers in independent claim 1.
Claim 50 recites that the α-TNFRSF antibodies can be selected from “Lob 7/6 heavy and light chains as disclosed in published US patent application US US20090074711; and heavy and light chain pairs disclosed in 2018094300”. The claim is indefinite because this information can be readily incorporated into the claim, akin to the rejection of claim 11 above. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant's convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)." MPEP 2173.05(s).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The claim recites that the polymers comprise monomers with some amino acid differences and/or (i) the particle comprises polymers are not homo-oligomers or (ii) each polymer in the particle is identical and each polymer is a homo-polymer. In essence, the claim requires that the polymers comprise monomers that are not identical or are identical. This does not further limit claim 1, which recites that the polymers have at least 90% sequence identity to any one of SEQ ID NO: 1-9, and, thus, must be identical or different from (within 90% identity) SEQ ID NO: 1-9.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 11, 21, 24, 32, and 49 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 32 is drawn to a kit comprising either a polypeptide comprising an amino acid sequence at least 90% identical to one of SEQ ID NO: 1-9, or a host cell expressing thereof, which is capable of (a) assembling into a homo-polymer (emphasis added). This rejection is based on the italicized limitation above, which does not disclose sufficient structure-function relationship to meet the written description requirement.
The claim requires that a polypeptide monomer with at least 90% identity to any one of SEQ ID NO: 1-9 covalently have the ability to assemble into a homo-polymer and bind to a constant region of an IgG antibody. The instant specification indicates that SEQ ID NO: 1-9 are made up of three distinct domains fused together - an Fc binding domain, a helical monomer to position the Fc binding domain relative to an oligomer domain, and an oligomer domain. Although the FC binding domains are derived from crystal structures known in the prior art, the oligomer domains, through which self-assembly is possible, were computationally developed and experimentally tested (see instant specification Appendix I). The core structure or the residue(s) of SEQ ID NO: 1-9 that directly facilitate homo-polymer assembly are predicted in the instant Table 2, but this would not allow one skilled in the art to recognize and know how to develop polypeptides with 90% or greater sequence identity to any of SEQ ID NO: 1-9 that retain the ability to assemble into homo-polymers. The claim also does not indicate any positional information (i.e., where sequence changes should occur) nor restrict the type of alterations (i.e., it does not specify that the alteration should be a conservative substitution).
Kelly et al. (US 20060058228, published 3/16/2006) discuss a phage display screen to identify peptides that distinguish between well-differentiated (HCT116) and poorly-differentiated (HT29) colon cancer cell lines. Analysis of the selected library resulted in the identification of a nine amino acid, disulfide-constrained peptide having a three amino acid (arg-pro-met, “RPM”) motif that specifically binds HT29 cells ([0032]). Substituting each of RPM with alanine significantly limited or abolished the ability of the peptide to compete with wild type RPM in a binding assay, indicating that these three residues alone accounted for the ability to bind to HT29 cells ([0034]). In contrast to this example, as described above, only residues predicted to be involved in homo-polymerization are known. Thus, one cannot accurately extrapolate how polypeptides with 90% sequence identity to SEQ ID NO: 1-9 might impact this functionality.
Further, Guo (H.H. Guo, J. Choe, & L.A. Loeb, Protein tolerance to random amino acid change, Proc. Natl. Acad. Sci. U.S.A. 101 (25) 9205-9210, (2004).) teaches that a protein’s tolerance to random substitutions ultimately depends on whether the residues at hand are involved the protein’s functional activity. For instance, regions that were highly substitutable in the human DNA repair enzyme 3-methyladenine DNA glycosylase (AAG) include the first 79 N-terminal residues previously demonstrated to be unnecessary for in vitro enzyme activity and DNA binding specificity. In contrast, residues that are involved in glycosylase function or DNA binding did not tolerate amino acid substitutions (“Substitutability and Structure”, Pg 9207-9209; Figure 1). Figure 1 of Guo also indicates that tolerated substitutions are generally conservative, i.e., a nonpolar residue is substituted for another nonpolar residue, etc. However, there are no explicit limitations in the instant claims regarding the type of alterations that can be made relative to SEQ ID NO: 1-9.
Applicants have not disclosed variants with 90% sequence identity to SEQ ID NO: 1-9.
SEQ ID NO: 1-9 range in length from 303-411 amino acids, omitting the optional residues. Polypeptide sequences having at least 90% sequence identity would require 273-370 of the amino acids to be maintained (i.e., 0.9*303=273; 0.9*411=370) and would allow up to 30-41 amino acids (i.e., 303-273 = 30; 411-370=41) to be substituted. Consequently, there are more than 2.37e^41 possible ways to select up to 30 residues from the 303 residues in the sequence and 5.58e^56 possible ways to select up to 41 residues from the 411 residues in the sequence that are free to be modified (i.e. x = n!/(r!(n-r)!)); each of which could be substituted with any of the other 19 naturally occurring common amino acids (i.e., that number multiplied by 19). The likelihood that all of these variant polypeptides would retain the recited function is low.
Consequently, it is unknown whether all variants with at least 90% sequence identity to any one of SEQ ID NO: 1-9 would retain the structural, chemical, and/or physical properties required to assemble into homo-polymers. Therefore, the instant specification does not provide adequate written description to possess the broad genus described above since the specification does not disclose a correlation between the necessary structure of the sequence and the claimed function to be maintained.
The above claims also recite multiple limitations using functional language, such as claim 1, which recites the α-Tie2 antibody, α-TNFRSF antibody, or an Ang F domain dimer in the plurality of antibodies/dimers non-covalently binds the polypeptide monomer chains, and claim 49, which recites the particle comprises the α-TNFRSF antibodies, wherein the antibodies target one or more of DR5, CD40, 4-1BB, and Tumor Necrosis Factor-like Weak Inducer of Apoptosis Receptor (TWEAKER). In essence, these claims recite antibodies based upon their function (their ability to bind polypeptide monomers and/or one or more of the targets above) rather than their structure (protein sequence). There is nothing in the claim to indicate the structural feature(s) required to meet this functional limitation, and describing an invention by function is insufficient to meet the written description requirement.
Per MPEP 2163(II)(3)(a), for some biomolecules, examples of identifying characteristics include a sequence, structure, binding affinity, binding specificity, molecular weight, and length. Although structural formulas provide a convenient method of demonstrating possession of specific molecules, other identifying characteristics or combinations of characteristics may demonstrate the requisite possession. As explained by the Federal Circuit, "(1) examples are not necessary to support the adequacy of a written description; (2) the written description standard may be met … even where actual reduction to practice of an invention is absent; and (3) there is no per se rule that an adequate written description of an invention that involves a biological macromolecule must contain a recitation of known structure." Falkner v. Inglis, 448 F.3d 1357, 1366, 79 USPQ2d 1001, 1007 (Fed. Cir. 2006); see also Capon v. Eshhar, 418 F.3d at 1358, 76 USPQ2d at 1084 ("The Board erred in holding that the specifications do not meet the written description requirement because they do not reiterate the structure or formula or chemical name for the nucleotide sequences of the claimed chimeric genes" where the genes were novel combinations of known DNA segments.). However, the claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
McVey and Beatty (Facts and Hopes of CD40 Agonists in Cancer Immunotherapy. Clin Cancer Res. 2025 Jun 3;31(11):2079-2087.; after Applicant’s priority date) describe examples of α-TNFRSF antibodies that target CD40, which are a promising class of immunotherapeutic agents that potentiate both innate and adaptive immunity (Abstract). Agonistic CD40 antibodies (mAbs) have been widely used with many ongoing clinical trials (Figure 2; for a subset of CD40 antibodies, see Table 2). McVey and Beatty describe how since the first-in-human use of CP-870,893 (selicrelumab) in 2007, second-generation CD40 mAbs have been developed by modifying the Fc domain, such as by incorporating IgG1 isotypes to encourage interaction with Fc γ receptors or by switching the isotype to IgG2, which can convert a CD40 antagonist to an Fc γ receptor-independent agonist; the agonistic conversion is dependent on the unique disulfide bonding properties of the IgG2 hinge (Pg 2081, right column, “Optimizing CD40 Agonists for Therapy”, second paragraph). Further, to reduce toxicity, bispecific antibodies targeting CD40 to specific tumors or stromal antigens can also be designed or through optimization of the Fc domain (Pg 2082, right column, last paragraph).
However, these few examples do not accurately capture the breadth of the claims recited in the functional language. In addition to the CD40 antibodies taught by McVey and Beatty, the claims recite additional antibody types and targets of antibodies, all of which are composed of unique amino acid sequences that impart unique 3D structure that can be targeted and/or bind proteins in different ways. Thus, based on the lack of structural limitations recited, any α-Tie2 antibody, α-TNFRSF antibody, or an Ang F domain dimer that targets any one of the above targets and/or binds to an Fc domain of a polypeptide monomer to any degree would meet the limitations of the instant claim.
Applicants have disclosed α-Tie2 and α-TNFRSF antibodies as well as Ang F domain dimers comprising at least 90% sequence identity to pairs of heavy and light chain sequences from SEQ ID NO: 11-56. No other are disclosed within the instant specification, and the claims listed above are written such that they contemplate or include additional compounds that retain the same functional characteristics beyond these limited examples. Thus, the instant specification does not provide adequate written description to possess the broad genus described above.
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 1, 2, 11, 16-17, 19, 21, 24, 32, 49, 50, and 63-76 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 4-6, 8, 10-13, 16, 24, 25, 29, 45, 48, and 49 of copending Application No. 17/907,372 (‘372 reference application; claim set filed 9/26/2022). Although the claims at issue are not identical, they are not patentably distinct from each other because they contain overlapping subject matter.
Claim 1 recites a polypeptide comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1-9, wherein residues in parentheses are optional (i.e.: not considered in the percent identity requirement), wherein the polypeptide is capable of (a) assembling into a polymer, including but not limited to a homo-polymer, and (b) binding a constant region of an IgG antibody. SEQ ID NO: 1-9 are identical to the instant SEQ ID NO: 1-9.
Dependent claims include conservation of certain residues in certain interfaces of SEQ ID NO: 1-9 (claims 2 and 3) and other substitutions (claims 4-6); C-terminal functional polypeptide (claim 8); nucleic acid, expression vectors, and host cells thereof (claims 10-12; reads on a host cell capable of expressing a polypeptide comprising an amino acid sequence, recited in the instant claim 32); a polymer of the polypeptide (claim 13); the polymer comprises a dimer, trimer, tetramer, or pentamer (claim 16); a particle comprising (a) a plurality of identical polymers and (b) a plurality of antibodies comprising Fc domains (claims 24, 25, and 29); a composition or pharmaceutical composition thereof (claims 45 and 48); and a method of using the particle for the diagnostic or therapeutic use of antibodies present in the particles and compositions (claim 49; the instant specification indicates particles can be used to treat disease or syndromes, Pg 3, lines 13-17). The instant particle comprising a plurality of polymers comprising monomers with at least 90% identity to any one of the instant SEQ ID NO: 1-9 and a plurality of α-Tie2 antibodies, α-TNFRSF antibodies, or Ang F domain dimers, all of which comprise Fc domains, anticipates the claims of copending Application No. ‘372.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/FRED H REYNOLDS/Primary Examiner, Art Unit 1658