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 invention Group I, claims 1-2, and 8, of the zipper forming protein sequence species ‘islet amyloid polypeptide sequence SEQ ID NO: 3’, and of the mussel foot protein sequence species ‘Mussel foot protein-5 Mfp5 sequence SEQ ID NO: 7’, in the reply filed on 12/04/2025 is acknowledged. Claims 9-11, 14, 19, 34-39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. It is noted that claim 8 is considered withdrawn since it does not read on the elected species ‘islet amyloid polypeptide sequence SEQ ID NO: 3 (FGAILSS). Claim 8 reads on the non-elected species Aβ-amyloid sequence SEQ ID NO: 4 (KLVFFAE), which comprises the ‘KLV’ motif recited in claim 8, line 1.
Claim Status
The amendment of 12/04/2025 has been entered. Claims 1-2, 8-11, 14, 19, and 34-39 are pending (claim set as filed on 12/04/2025). Claims 9-11, 14, 19, 34-39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claim 8 is withdrawn since it does not read on the elected species ‘islet amyloid polypeptide sequence SEQ ID NO: 3’, as discussed above under Election/Restrictions. Election was made without traverse in the reply filed on 12/04/2025.
Claims 1-2 are currently under examination and were examined on their merits.
Priority
This application filed on 02/27/2023 claims priority to PCT application no. PCT/US21/47593, filed on 08/25/2021, and to provisional application no. PRO 63/069,987, filed on 08/25/2020.
Information Disclosure Statement
The Information Disclosure Statements (IDS) filed on 05/08/2025 and 04/28/2025 have been received and considered.
Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 2 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites “(SEQ ID NO: 1)”, “(SEQ ID NO: 2)”, “(SEQ ID NO: 3)”, “(SEQ ID NO: 4)”, “(SEQ ID NO: 5)”, “(SEQ ID NO: 6)”, and “(SEQ ID NO: 7)” which renders the claim indefinite since it is unclear if the recited SEQ ID numbers in parentheses are part of the claim scope, or are merely recited as exemplary SEQ ID numbers for the broader embodiments claimed.
Claim 2 recites “mussel foot protein-3 Mfp3 sequence (SEQ ID NO: 6)” and “mussel foot protein-6 Mfp-6 sequence (SEQ ID NO: 6)”, which renders the claim indefinite since it is unclear if SEQ ID NO: 6 refers to a mussel foot protein-3 Mfp3 sequence or to a mussel foot protein-6 Mfp-6 sequence.
One of ordinary skill in the art would not be able to determine the metes and bounds of claim 2, and thus, could not clearly determine how to avoid infringement of the claim.
In the interest of compact prosecution, claim 2 is interpreted to the broadest embodiment claimed.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 2 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim 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.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. Claim 2 is directed in part to a genus of islet amyloid polypeptide sequence fragments or variants of the elected polypeptide SEQ ID NO: 3 and to a genus of mussle foot protein -5 Mfp5 sequence fragments or variants of the polypeptide SEQ ID NO: 7, wherein the structure of the recited fragments and variants is not further specified.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
There is either (a) no structural limitation, or (b) a significant amount of structural variability with respect to the members of the genus of islet amyloid polypeptide sequence fragments or variants and of the genus of mussel foot protein -5 Mfp5 sequence fragments or variants required by the claims.
While the specification in the instant application discloses the structure of islet amyloid polypeptide sequence SEQ ID NO: 3 and of the mussel foot protein-5 Mfp5 sequence SEQ ID NO: 7, it provides no clue as to the structural elements required in any islet amyloid polypeptide fragment or variant or in any mussel foot protein - 5 Mfp5 sequence fragment or variant, nor does it teach which structural elements within SEQ ID NO: 3 and SEQ ID NO: 7 are required in any islet amyloid fragment or variant, and any mussel foot protein -5 Mfp5 fragment or variant, respectively. Moreover, while the specification describes wherein hybrid proteins comprising fragments or variants of SEQ ID NO: 3 and of SEQ ID NO: 7, are used to form adhesive hydrogel compositions (specification, paragraphs [0004], [0007], [0031], [0032], [0038]), the specification and prior art are silent to those structural features in any islet amyloid protein or any mussel foot protein-5 Mfp5 fragment, that are associated with the functional properties required for making a hybrid protein that forms an adhesive hydrogel. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which fragments or variants of the polypeptides of SEQ ID NO: 3 or SEQ ID NO: 7 would have the desired properties to make a hybrid protein that forms an adhesive hydrogel.
The claims encompass a large genus of proteins which are structurally unrelated or substantially unrelated in structure, since neither the fragment length nor sequence identity is specified for fragments or variants derived from SEQ ID NO: 3 and SEQ ID NO: 7. A sufficient written description of a genus of polypeptides may be achieved by a recitation of a representative number of polypeptides defined by their amino acid sequence or a recitation of structural features common to members of the genus. However, in the instant case, there are no specific fragments or variants derived from SEQ ID NO: 3 or SEQ ID NO: 7 described in the instant application, and no structural feature is described which is representative of all the members of the recited genus of proteins. It is further noted that the art teaches how even highly structurally homologous polypeptides can have different functional properties. For example, Fox et al. (“Selection for Nonamyloidogenic Mutants of Islet Amyloid Polypeptide (IAPP) Identifies an Extended Region for Amyloidogenicity”, published in 2010, Biochemistry, Vol. 49, pages 7783–7789), teaches wherein single amino acid substitutions in human islet amyloid polypeptide can affect the polypeptide to become non-amyloidogenic (see entire document, including abstract and Fig. 2), thereby emphasizing the need of either recitation of a representative number of polypeptides defined by their amino acid sequence, or of recitation of structural features common to members of the genus.
Due to the fact that the specification discloses no species of fragments or variants derived from islet amyloid polypeptide SEQ ID NO: 3 and no species of fragments or variants derived from Mfp5 protein SEQ ID NO: 7 required by the claims, and the lack of description of species by any relevant, identifying structural characteristics or properties that are required for the desired function of the polypeptides or proteins in a hybrid protein forming an adhesive hydrogel, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claim Rejections - 35 USC § 103
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.
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al. (US 2016/0220727 A1, published on 08/04/2016), hereinafter ‘Lu’, in view of Dai et al. (“Fibril Self-Assembly of Amyloid−Spider Silk Block Polypeptides”, published on 04/17/2019, Biomacromolecules, Vol. 20, pages 2015−2023, and Supplementary Materials, pages 1-22), hereinafter ‘Dai’, as evidenced by Perov et al. (“Structural Insights into Curli CsgA Cross-β Fibril Architecture Inspire Repurposing of Anti-amyloid Compounds as Anti-biofilm Agents”, published on 08/30/2019, PLOS Pathogen, 15(8): e1007978), hereinafter ‘Perov’.
Lu’s general disclosure relates to novel fusion proteins comprising an adhesive domain and an amyloid domain (see entire document, including abstract).
Regarding claim 1, pertaining to the hybrid protein, Lu teaches a hybrid protein comprising an amino sequence (“recombinant fusion proteins (e.g., …Mfp5-CsgA)” ; paragraph [0004], see claim 1), the amino acid sequence comprising:
an amyloid protein CsgA (“Mfp5-CsgA”, “functional amyloid adhesive from E. coli ( e.g., CsgA, subunit for Curli amyloid”; paragraph [0004]). It is noted that CsgA intrinsically comprises at least two zipper-forming protein sequences, as evidenced by Perov (“we elucidated atomistic structural features of CsgA spine segments. Specifically, the R1 45LNIYQY50 and 47IYQYGG52 segments and the R5 137VTQVGF142 segment formed fibrils that bound the amyloid indicator dye ThT and formed canonical amyloid class 1 steric zippers”; page 9, paragraph 2).
a mussel foot protein sequence (“mussel foot protein (Mfp)”; paragraph [0005]), the mussel foot protein positioned at a C-terminus or an N-terminus of the amyloid protein CsgA (“In some embodiments, Mfp3 or Mfp5 is fused to the C-terminus of CsgA, Mfp3 or Mfp5 is fused to the N-terminus of CsgA, or …”; paragraph [0005]),
In addition, Lu teaches wherein individual components of the fusion protein can be connected via a flexible peptide linker ("In some embodiments, the individual components of the fusion protein ( e.g., a Mfp and amyloid protein) are directly linked to each other through an amide bond. In other embodiments, they are joined via a linker, preferably a peptidic linker or an organic linker ... Preferably, a peptide linker will introduce some structural flexibility between components to be linked."; paragraph [0083]).
Regarding claim 2, please note the elected mussel foot protein sequence species ‘Mussel foot protein-5 Mfp5 sequence SEQ ID NO: 7’ under Election/Restriction above.
Pertaining to the mussel foot protein, Lu teaches wherein the mussel foot protein is mussel foot protein Mfp5 (paragraph [0005]), wherein the sequence of Lu’s Mfp5 (SEQ ID NO: 4) has an insertion between positions 17 and 18 of instant SEQ ID NO: 7 (please see alignment below), and therefore, Lu’s Mfp5 is a variant of the instant Mfp5 (SEQ ID NO: 7).
In addition, Lu teaches the use of novel fusion protein-based adhesives for use in medical and marine applications (see abstract).
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Lu does not teach wherein the hybrid protein comprises at least one flexible sequence from a spider silk protein sequence, wherein each of the at least one flexible sequence is positioned between each pair of the at least two zipper-forming protein sequences to form a repeated sequence (instant clam 1), and wherein each of the at least two zipper-forming protein sequences is selected from the elected islet amyloid polypeptide sequence (SEQ ID NO: 3), any fragment thereof, and any variant thereof, and wherein each of the at least one flexible sequence from a spider silk protein sequence comprises a glycine-rich sequence from a Nephila clavipes MaSp1 dragline spidroin (SEQ ID NO: 5) (instant claim 2). Please note the elected zipper forming protein sequence species ‘islet amyloid polypeptide sequence SEQ ID NO: 3’ under Election/Restrictions above.
Dai’s general disclosure relates to block polypeptides, each containing 16 repeats of a zipper-forming segment from four different amyloid morphological classes (see entire document, including abstract).
Regarding claim 1, pertaining to the at least two zipper-forming protein sequences and the at least one flexible sequence from a spider silk protein sequence, Dai teaches a sequence comprising 16 repeats of alternating amyloid peptides and spider silk linker peptides (page 2017, left column, paragraph 4; see Fig. 1a and amino acid sequences SNQ-16X, GDV-16X, FGA-16X, KLV-16X in Supplementary Materials, pages 4-5).
Regarding claim 2, pertaining to the at least two zipper-forming protein sequences and the at least one flexible sequence from a spider silk protein sequence, Dai teaches wherein the zipper forming protein sequences in a block polypeptide are the islet amyloid polypeptide sequence (instant SEQ ID NO: 3, ‘FGAILSS’) (page 2017, left column, paragraph 4; see amino acid sequence FGA-16X in Supplementary Materials, pages 4-5). Dai further teaches wherein each flexible sequence comprises a glycine-rich sequence from a Nephila clavipes MaSp1 dragline spidroin (instant SEQ ID NO:5) (page 2017, left column, paragraph 3; see amino acid sequence FGA-16X in Supplementary Materials, pages 4-5). Please see below the alignment of instant SEQ ID NO: 5 with Lu’s glycine-rich sequence from page 2017, left column, paragraph 3.
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In addition, Dai teaches that “amyloid fibrils have also been discovered to have various functional roles throughout nature, such as in surface adhesion and interaction”, and that synthesis of proteins containing multiple β-sheet-forming peptides could lead to novel fibril materials with higher stability and complexity, expanding the capability of amyloid-based
Bionanomaterials” (page 2015, right column, paragraph 1 - page 2016, left column, paragraph 1).
While Lu does not teach wherein the hybrid protein comprises at least one flexible sequence from a spider silk protein sequence, wherein each of the at least one flexible sequence is positioned between each pair of the at least two zipper-forming protein sequences to form a repeated sequence (instant clam 1), and wherein each of the at least two zipper-forming protein sequences is selected from the elected islet amyloid polypeptide sequence (SEQ ID NO: 3), any fragment thereof, and any variant thereof, wherein each of the at least one flexible sequence from a spider silk protein sequence comprises a glycine-rich sequence from a Nephila clavipes MaSp1 dragline spidroin (SEQ ID NO:5) (instant claim 2), it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified Lu’s hybrid protein with Dai’s teachings on block polypeptides comprising 16 repeats of a zipper forming protein sequence alternating with flexible sequences from a spider silk protein sequence, in order to have created a hybrid protein wherein the flexible sequences are from a spider silk protein sequence, wherein each of the flexible sequences is positioned between each pair of the two zipper-forming protein sequences to form a repeated sequence (instant claim 1), further wherein each of the zipper-forming protein sequences is selected from an islet amyloid polypeptide sequence (SEQ ID NO:3), wherein each of the at least one flexible sequence from a spider silk protein sequence comprises a glycine-rich sequence from a Nephila clavipes MaSp1 dragline spidroin (SEQ ID NO: 5). One would have been motivated to do so, in order to create a superior bioadhesive with improved stability (Dai, page 2015, right column, paragraph 1 - page 2016, left column, paragraph 1). A skilled artisan would have reasonably expected success in combining Lu’s teachings with Dai’s teachings since both references are directed to biomaterials comprising zipper-forming protein sequences.
Conclusion
No claims are allowed.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA ZINGARELLI whose telephone number is (703)756-1799. The examiner can normally be reached M-F 9-5.
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/SANDRA ZINGARELLI/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653