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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/25/2025 has been entered.
Claim Status
The amendment of 11/25/2025 has been entered. Claims 1-3, 7, 12, 17, 23, 25, 37, 40-42, 45-46, 49, 52, and 68-69 are pending (claim set as filed on 11/25/2025). Claims 40-42, 45-46, 49, 52, and 68-69 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant previously elected invention Group I, claims 1-3, 7, 12, 17, 23, 25, 37, drawn to a method of producing biopolymer particles coated with a fusion protein, and polymer species ‘PHA’, the particle isolation method species ‘cell sorter’, the extracellular vesicle binding domain species ‘antibody’, and the method species a) for making a biopolymer coated particle, in the reply filed on 11/18/2024.
Claims 1-3, 7, 12, 17, 23, 25, 37 are currently under examination and were examined on their merits.
Claim Interpretation
The instant claims recite numerous optional limitations. Please note that optional language is not required by the claims, and so any prior art that reads on the required claim limitations will be interpreted to read on the entireties of the instant claims, regardless of whether the prior art recites the optional limitations.
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.
Claims 1-3, 7, 12, 17, 23, 25, 37 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 pre-AIA 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 1 is directed in part to a genus of PhaR-derived binding domain variants of the polypeptide of SEQ ID NO: 2 that have at least 70% sequence identity to the polypeptide of SEQ ID NO: 2.
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 biopolymer binding domain polypeptides required by the claims. While the specification in the instant application discloses the structure of the PhaR-derived binding domain polypeptide of SEQ ID NO: 2, it provides no clue as to the structural elements required in any binding PhaR-derived binding domain protein, nor does it teach which structural elements within SEQ ID NO: 2 are required in any PhaR-derived binding domain protein. Moreover, while the specification and claims require PhaR-derived binding domain variants to have biopolymer binding properties, the specification is silent to those structural features in any PhaR-derived binding domain protein, that are associated with these functional properties. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which variants of the polypeptide of SEQ ID NO: 2 having the recited % sequence identity have the desired biopolymer binding properties.
The claims encompass a large genus of proteins which are structurally unrelated or substantially unrelated in structure. A polypeptide having 70% sequence identity with the polypeptide of SEQ ID NO: 2 allows for any combination of 27 amino acid modifications within SEQ ID NO: 2 (27.6 = 0.3x92; SEQ ID NO: 2 has 92 amino acids). The total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula N!x19A/(N-A)!/A!, where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. Thus, the total number of variants of the polypeptide of SEQ ID NO: 2 having 70% sequence identity to the polypeptide of SEQ ID NO: 2 that result from amino acid substitutions is 92!x1927/(92-27)!/27! or 4.65x1057 variants. 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, which features constitute a substantial portion of the genus. However, in the instant case, there is either no recited structural feature which is representative of all the members of the genus of proteins recited, or the recited structural feature, i.e., 70% sequence identity to SEQ ID NO: 2 is not representative of all the members of the genus of PhaR-derived binding domain recited since there is no information as to which are the structural elements within the polypeptide of SEQ ID NO: 2 that are essential for the recited activity, which are the remaining structural elements required in the recited polypeptides in addition to those recited in the claims such that the desired biopolymer binding activity is displayed, or a correlation between structure and function which would provide those unknown structural features.
Due to the fact that the specification only discloses SEQ ID NO: 2 of the genus of PhaR-derived binding domain proteins required by the claims, and the lack of description of any additional PhaR-derived binding domain variants by any relevant, identifying characteristics or properties, 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 § 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.
Claims 1-3, 7, 12, 17, 23, 25, 37 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 1 recites “the fusion protein comprises a biopolymer particle binding domain
and an extracellular vesicle binding domain, a linker sequence between the biopolymer particle
binding domain and extracellular vesicle binding domain, and sequence capable of being cleaved by a protease, […], wherein the biopolymer particle binding domain is a PhaR-derived binding domain (PBD), wherein the domain consists of SEQ ID NO: 2, or consists of a sequence that has at least 70% sequence identity to SEQ ID NO: 2”, which renders the claim indefinite, since it is unclear due to the comprising and consisting language of claim 1, which other sequence features the fusion protein may comprise, for example, if the fusion protein may comprise other PhaR-derived sequence features in addition to the PhaR-derived binding domain which consists of SEQ ID NO: 2, or consists of a of a sequence that has at least 70% sequence identity to SEQ ID NO: 2.
One of ordinary skill in the art would not be able to determine the metes and bounds of the claim, and thus, could not clearly determine how to avoid infringement of claim 1.
Dependent claims 2-3, 7, 12, 17, 23, 25, and 37 are indefinite since they do not remedy the indefinite language of claim 1.
In the interest of compact prosecution, claim 1 is interpreted to the broadest embodiment claimed.
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.
Claims 1-3, 7, 12, 17, 23, 25, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Rehm et al. (US 2011/0124516 A1, published on 05/26/2011), hereinafter ‘Rehm’, in view Popovic et al. (“Isolation of anti-extra-cellular vesicle single-domain antibodies by direct panning on vesicle-enriched fractions”, published on 01/13/2018, Microb Cell Fact, Vol. 17, Article number 6, pages 1-13), hereinafter ‘Popovic’, and in view of Zhang et al. (“Microbial polyhydroxyalkanote synthesis repression protein PhaR as an affinity tag for recombinant protein purification”, published on 05/10/2010, Microbial Cell Factories 2010, Vol. 9, Article number 28, pages 1-6), hereinafter ‘Zhang’.
Rehm’s general disclosure relates to “functionalised polymer particles, processes of production and uses thereof” (see entire document, including abstract).
Regarding claims 1-3, 7, 12, 17, 23, 25, and 37, please note the rejection under Claim Rejections - 35 USC § 112 (b) above.
Regarding claim 1, pertaining to a method of producing biopolymer particles, Rehm teaches a method of producing biopolymer particles coated with a fusion protein (“The present invention relates to functionalised polymer particles, processes of production and uses thereof”, “Functionalised polymer particles may comprise one or more surface-bound fusion polypeptides”; paragraph [0420]), wherein the method comprises the steps of:
Providing a host cell comprising
a PHA production module (paragraphs [0040]-[0042], [0321], [0470]); and
a secondary module encoding a fusion protein capable of coating the biopolymer particles in the cells (paragraphs [0236]-[0237], [0565], [0782], [0919]; see Fig. 21; it is noted that Fig. 21 shows fusion protein coated biopolymer particles inside the microbial cell), wherein the fusion protein comprises a biopolymer particle binding domain and a target-binding domain (paragraphs [0546]-[0548], [0351], [0700]), a linker sequence between the biopolymer particle binding domain and target- binding domain (paragraph [0566]), and sequence capable of being cleaved by a protease (paragraphs [0566]-[0567]), wherein the linker is about 100 amino acids in length (paragraph [0854]).
cultivating the host cell under conditions suitable for the production of biopolymer particles coated with the fusion protein (paragraphs [0565], [0688]).
Regarding claim 2, pertaining to isolating coated biopolymer particles, Rehm teaches isolating the coated biopolymer particles from the host cell (paragraphs [0714], [0782], [0919]; see Fig. 21; note by Examiner, Fig. 21 shows isolated antigen-displaying PHA granules).
Regarding claim 3, please note the elected species ‘PHA’ under Claim Status above.
Pertaining to the biopolymer particle, Rehm teaches wherein the biopolymer particle comprises polyhydroxyalkanoate (PHA) (paragraph [0639]).
Regarding claim 7, pertaining to a nucleic acid construct, Rehm teaches wherein
the host cell comprises:
A biopolymer particle production nucleic acid construct (paragraphs [0040]-[0042], [0470]), and
A fusion protein production nucleic acid construct (paragraph [0236]), and
the host cell is a bacterial cell (paragraph [0446]).
Regarding claim 12, please note the elected species ‘cell sorter’ under Claim Status above.
Pertaining to the isolation of the biopolymer particles, Rehm teaches wherein
the biopolymer particles are isolated from the host cell by disrupting the cell
and isolating the particles (paragraph [0714]);
the isolating the particles is performed using a cell sorter (paragraph [0714]).
Regarding claim 17, pertaining to the mean diameter of the uncoated biopolymer particle and to the percentage of particle surface coated with the fusion protein, Rehm teaches
wherein the mean diameter of the uncoated biopolymer particle is:
less than 400 nm (“In some preferred embodiments the polymer particles have a diameter below about 300 nm, below about 200 nm, below about 150 nm, or below about 105 nm.”; paragraph [0691]), and
wherein at least 5%, 10%, 20%, 30%, 40%, 50%, or at least 60% of the surface is coated with the fusion protein (paragraph [0672]).
Regarding claim 23, pertaining to the number of coated biopolymer particles per host cell, Rehm teaches wherein
the host cell comprises at least about 20, 30, 40, 50 or at least about 60 biopolymer particles (paragraph [0699]).
Regarding claim 25, please note the elected species ‘PHA’ under Claim Status above. Pertaining to the biopolymer binding domain, Rehm teaches wherein
the biopolymer binding domain comprises a domain capable of binding to polyhydroxyalkanoate (PHA) (paragraphs [0316], [0459]).
Regarding claim 37, pertaining to at least two different fusion protein coated biopolymer particles, Rehm teaches wherein the method produces at least two different fusion protein coated biopolymer particles (paragraphs [0048], [0220]).
In addition, Rehm discloses that PhaR binds to the surface of the formed polymer particles (paragraph [0469]). Rehm further teaches that “polyhydroxyalkyl polymer particles can be stably maintained as particles outside the host cell that produced them, and that these particles can be designed to suit a number of applications” (paragraph [0716]), and that “[f]unctionalised polymer particles may comprise one or more surface-bound fusion polypeptides” (paragraph [0717]). Rehm discloses a fusion polypeptide comprising a binding site that allows for isolation of target components (paragraphs [0438], [0748]-[0750]), that “a mixed population of polymer particles and/or polymer particles displaying a mixed population of fusion polypeptides can be used to screen a sample for a plurality of different target components”, and that “the use of fluorescence-activated cell sorting (FACS) in muliplex analyses using polymer particles of the invention allows detecting and optionally isolating antigen-specific and quantitative levels of target components in a sample (paragraph [0795]).
Rehm does not teach
wherein the fusion protein comprises an extracellular vesicle binding domain sequence (instant claim 1), wherein the extracellular vesicle binding domain is the elected antibody (claim 25),
wherein the biopolymer particle binding domain is a PhaR-derived binding domain (PBD), wherein the domain consists of SEQ ID NO: 2, or consists of a sequence that has at least 70% sequence identity to SEQ ID NO: 2 (instant claim 1),
wherein the linker is >100 amino acids in length (instant claim 1),
wherein the host cell comprises at least about 20, 30, 40, 50 or at least about 60 coated biopolymer particles (instant claim 23).
Popovic’s general disclosure relates to the “isolation of anti-EV nanobodies for the use in immunoaffinity-based EV capture” (see entire document, including abstract; note, EV, extracellular vesicle).
Regarding claims 1 and 25, please note the rejection under Claim Rejections - 35 USC § 112 (b) above, and the elected species ‘antibody’ under Claim Status above.
Pertaining to the extracellular vesicle binding domain, Popovic teaches an antibody that can bind to CD9 of extracellular vesicles (page 2, left column, paragraph 2; page 5, left column, paragraph 1; see title and abstract).
In addition, Popovic teaches wherein the EV binding single domain antibodies were used for EV capture (page 9, left column, paragraph 3; see abstract).
Zhang’s general disclosure relates to PhaR-intein-target fusion proteins (see entire document, including abstract).
Regarding claim 1, please note the rejection under Claim Rejections - 35 USC § 112 (b) above.
Pertaining to a PhaR-derived binding domain, Zhang teaches PhaR fusion proteins with the ability to bind to PHA biopolymer, wherein the biopolymer binding domain of the fusion protein is a PhaR-derived binding domain (page 5, right column, paragraph 3; see abstract and Fig. 2A). It is noted that Zhang’s PhaR relates to PhaR from Ralstonia eutropha H16 (page 2, left column, paragraph 4), wherein PhaR (183 amino acids) from Ralstonia eutropha H16 comprises instant SEQ ID NO: 2, as shown in the alignment below.
In addition, Zhang teaches that a “[p]revious study proved PhaR was able to tightly attach to both artificial amorphous and crystalline PHB granules in vitro”, “that PhaR has a PHB
granule binding domain”, and that “PhaR was reported to bind to the surface of polyethylene, polystyrene and poly-lactic acid, which shows the binding is non-specific, mainly by hydrophobic interaction” (page 1, right column, paragraph 1). Zhang further teaches that “[c]omparable to several other PHA bind proteins including PhaP, PhaZ and possibly PhaC, PhaR, as an affinity tag, is at least as good as others for pure recombinant protein production”, that “PhaR (20 kDa) is smaller than PhaP (21 kDa), PhaZ (45 kDa) and PhaC (65 kDa) in Ralstonia eutropha H16,” and “therefore, its expression and accumulation should be more effective and richer compared with others” (page 5, right column, paragraph 3).
GenCore version 6.5.2
Copyright (c) 1993 - 2026 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: March 3, 2026, 18:53:30 ; Search time 120 Seconds
(without alignments)
53348.229 Million cell updates/sec
Title: US-17-762-931-2
Perfect score: 477
Sequence: 1 MFSSAMLSQIIRFYGHAMQG..........MSNYIEQSKNLFVQMQEQMQ 92
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 182486956 unique seqs, 69584646596 residues
Total number of hits satisfying chosen parameters: 182486956
Minimum DB seq length: 0
Maximum DB seq length: 2000000000
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 45 summaries
Database : UniProt_202504:*
===================================
RESULT 1: 1 DUPLICATE:
===================================
%
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
1 477 100.0 183 O68272_CUPNE -- 1 SubName: Full=PhbF {ECO:0000313|EMBL:AAC38319.1};
ALIGNMENT:
Query Match 100.0%; Score 477; Length 183;
Best Local Similarity 100.0%;
Matches 92; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MFSSAMLSQIIRFYGHAMQGMMGTYLEKNIQAFIDIQNKLAENSKGLYSGETFSPDMWSQ 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 74 MFSSAMLSQIIRFYGHAMQGMMGTYLEKNIQAFIDIQNKLAENSKGLYSGETFSPDMWSQ 133
Qy 61 FMNMQGPMMQGMMSNYIEQSKNLFVQMQEQMQ 92
||||||||||||||||||||||||||||||||
Db 134 FMNMQGPMMQGMMSNYIEQSKNLFVQMQEQMQ 165
DUPLICATES:
Q0KBP6_CUPNH
ID Q0KBP6_CUPNH Unreviewed; 183 AA.
AC Q0KBP6;
DT 03-OCT-2006, integrated into UniProtKB/TrEMBL.
DT 03-OCT-2006, sequence version 1.
DT 02-APR-2025, entry version 72.
DE SubName: Full=Polyhydroxyalkanoate synthesis repressor PhaR {ECO:0000313|EMBL:QCC00459.1};
DE SubName: Full=Transcriptional regulator of phasin expression {ECO:0000313|EMBL:CAJ92575.1};
GN Name=phaR {ECO:0000313|EMBL:CAJ92575.1};
GN OrderedLocusNames=H16_A1440 {ECO:0000313|EMBL:CAJ92575.1};
GN ORFNames=E6A55_07270 {ECO:0000313|EMBL:QCC00459.1};
OS Cupriavidus necator (strain ATCC 17699 / DSM 428 / KCTC 22496 / NCIMB 10442
OS / H16 / Stanier 337) (Ralstonia eutropha).
OC Bacteria; Pseudomonadati; Pseudomonadota; Betaproteobacteria;
OC Burkholderiales; Burkholderiaceae; Cupriavidus.
OX NCBI_TaxID=381666 {ECO:0000313|EMBL:CAJ92575.1, ECO:0000313|Proteomes:UP000008210};
RN [1] {ECO:0000313|EMBL:CAJ92575.1, ECO:0000313|Proteomes:UP000008210}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 17699 / DSM 428 / KCTC 22496 / NCIMB 10442 / H16 / Stanier
RC 337 {ECO:0000313|Proteomes:UP000008210}, and H16
RC {ECO:0000313|EMBL:CAJ92575.1};
RX PubMed=16964242; DOI=10.1038/nbt1244;
RA Pohlmann A., Fricke W.F., Reinecke F., Kusian B., Liesegang H., Cramm R.,
RA Eitinger T., Ewering C., Potter M., Schwartz E., Strittmatter A., Voss I.,
RA Gottschalk G., Steinbuechel A., Friedrich B., Bowien B.;
RT "Genome sequence of the bioplastic-producing 'Knallgas' bacterium Ralstonia
RT eutropha H16.";
RL Nat. Biotechnol. 24:1257-1262(2006).
RN [2] {ECO:0000313|EMBL:QCC00459.1, ECO:0000313|Proteomes:UP000296079}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=H16 {ECO:0000313|EMBL:QCC00459.1,
RC ECO:0000313|Proteomes:UP000296079};
RA Little G.T., Ehsaan M., Arenas-Lopez C., Jawed K., Winzer K., Kovacs K.,
RA Malys N., Minton N.P.;
RT "Long-read de novo sequencing of Cupriavidus necator H16.";
RL Submitted (APR-2019) to the EMBL/GenBank/DDBJ databases.
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DR EMBL; AM260479; CAJ92575.1; -; Genomic_DNA.
DR EMBL; CP039287; QCC00459.1; -; Genomic_DNA.
DR RefSeq; WP_010810130.1; NZ_CP039287.1.
DR AlphaFoldDB; Q0KBP6; -.
DR SMR; Q0KBP6; -.
DR STRING; 381666.H16_A1440; -.
DR KEGG; reh:H16_A1440; -.
DR PATRIC; fig|381666.6.peg.1829; -.
DR eggNOG; COG5394; Bacteria.
DR HOGENOM; CLU_089210_1_0_4; -.
DR OrthoDB; 9795345at2; -.
DR Proteomes; UP000008210; Chromosome 1.
DR Proteomes; UP000296079; Chromosome 1.
DR GO; GO:0006355; P:regulation of DNA-templated transcription; IEA:InterPro.
DR InterPro; IPR012909; PHA_DNA-bd_N.
DR InterPro; IPR010134; PHA_reg_PhaR.
DR InterPro; IPR007897; PHB_accumulat.
DR NCBIfam; TIGR01848; PHA_reg_PhaR; 1.
DR Pfam; PF05233; PHB_acc; 2.
DR Pfam; PF07879; PHB_acc_N; 1.
PE 4: Predicted;
KW Reference proteome {ECO:0000313|Proteomes:UP000008210}.
FT DOMAIN 11..70
FT /note="PHA accumulation regulator DNA-binding N-terminal"
FT /evidence="ECO:0000259|Pfam:PF07879"
FT DOMAIN 75..113
FT /note="PHB accumulation regulatory"
FT /evidence="ECO:0000259|Pfam:PF05233"
FT DOMAIN 126..165
FT /note="PHB accumulation regulatory"
FT /evidence="ECO:0000259|Pfam:PF05233"
SQ SEQUENCE 183 AA; 20985 MW; ACE6D58653387CD6 CRC64;
While Rehm does not teach wherein the fusion protein comprises an extracellular vesicle binding domain (instant claim 1), wherein the extracellular vesicle binding domain is an antibody (instant claim 25), it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method for producing fusion protein coated biopolymer particles as taught by Rehm with the extracellular vesicle binding single-domain antibody taught by Popovic, in order to develop a method for producing biopolymer particles coated with fusion proteins comprising an extracellular vesicle binding antibody. One would have been motivated to do so because the fusion polypeptide taught by Rehm can be modified with a target binding domain (Rehm, paragraph [0351]), and because PHA particles are stable outside the host cell and can be designed for a number of applications (Rehm, paragraph [0716]). A skilled artisan would have reasonably expected success in combining Rehm’s and Popovic’s teachings for the benefit of improved capture of extracellular vesicles, since both references are directed to binding a target component.
While modified Rehm does not teach wherein the biopolymer particle binding domain is a PhaR-derived binding domain (PBD), wherein the domain consists of SEQ ID NO: 2 or consists of a sequence that has at least 70% sequence identity to SEQ ID NO: 2 (instant claim 1), 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 Rehm’s method with Zhang’s PhaR which comprises instant SEQ ID NO: 2, in order to create a method wherein the fusion protein comprises a biopolymer particle binding domain which is a PhaR-derived binding domain consisting of SEQ ID NO: 2. It is noted that modified Rehm’s fusion protein comprising Zhang’s PhaR inherently comprises the instantly recited PhaR-derived binding domain (PBD) consisting of SEQ ID NO: 2. One would have been motivated to modify Rehm’s method with Zhang’s PhaR to improve polymer binding and expression of the fusion protein (see Zhang, page 1, right column, paragraph 1, and page 5, right column, paragraph 3). A skilled artisan would have reasonably expected success in combining Rehm’s and Zhang’s teachings since both references are directed to fusion polypeptides binding to biopolymer particles.
While modified Rehm does not teach wherein the linker is >100 amino acids in length (instant claim 1), the instantly recited linker length would be within the realm of routine experimentation since Rehm teaches a linker length of about 100 amino acids (paragraph [0854]). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to determine the optimal linker length, in order to optimize folding of the fusion polypeptides (Rehm, paragraph [0854]), and thus improve binding of the fusion protein to the biopolymer and to the extracellular vesicles. Further, one would expect success since Rehm’s teachings are directed to fusion proteins comprising different fusion partners (paragraph [0083]), and therefore, manipulation of the linker length would be within the purview of an artisan. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA1955) (see MPEP § 2144.05 part II A).
While modified Rehm does not expressly teach wherein the host cell comprises at least about 20, 30, 40, 50 or at least about 60 coated biopolymer particles (instant claim 23), it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined modified Rehm’s teachings of at least about 20, 30, 40, 50 or at least about 60 biopolymer particles per host cell with fusion polypeptides that bind to biopolymer particles as taught by Rehm (see above), in order to provide a method that produces at least about 20, 30, 40, 50 or at least about 60 coated biopolymer particles number per host cell. One would have been motivated to do so, since Rehm teaches wherein polymer particles displaying fusion polypeptides can be used for detecting and isolating target components (paragraphs [0438], [0748]-[0750]). A skilled artisan would have reasonably expected success in the combination of Rehm’s teachings for the benefit of maximizing the number of fusion polypeptide coated biopolymer particles that can be used for target binding and isolation.
Response to Arguments
Applicant has traversed the previous rejection of claims 1-3, 7, 12, 17, 23, 25, 37 under 35 U.S.C. 103 in the reply filed on 11/25/2025 (remarks, pages 17-23). Rehm, Popovic, and Zhang are still relied upon in the above rejections. Applicants arguments have been fully considered but they are not persuasive.
Applicant states that Zhang teaches “fusion constructs with the full-length PhaR sequence” (remarks, page 19), that “SEQ ID NO: 2 (92 residues) is significantly smaller than the full-length sequence (183 residues)” (remarks, page 20), and that “[t]runcated PhaR is advantageous”( remarks, page 21).
The Examiner responds, that as discussed above under Claim Rejections - 35 USC § 112 (b), due to the indefinite language in claim 1, it is unclear if the fusion protein can comprise other sequence features of PharR in addition to SEQ ID NO: 2. As such, the claim is interpreted to the broadest embodiment claimed.
If Applicant intended to claim a fusion protein consisting of specific sequences or excluding specific sequences, these features are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant describes that “the assertion that suitable linker length could be identified through routine experimentation is unfounded” (remarks, page 22).
The Examiner responds that as discussed above under Claim Rejections - 35 USC § 103, the optimal linker length would be within the realm of routine experimentation, since Rehm teaches a linker length of about 100 amino acids (paragraph [0854]). It is noted that a linker length of about 100 amino acids” (paragraph [0854]) includes linkers that are >100 amino acids in length. It would have been obvious to a skilled artisan to determine the optimal linker length for optimized folding of the fusion polypeptides (Rehm, paragraph [0854]). Due to Rehm’s teachings on fusion proteins comprising different fusion partners (paragraph [0083]), manipulation of the linker length would be within the purview of an artisan.
Applicant concludes that “one of ordinary skill in the art would not modify the combination of Rehm, Popovic and Zhang to arrive at the claims as amended” (remarks, page 23).
The Examiner responds that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, regarding claim 1, Rehm teaches a method of producing biopolymer particles coated with a fusion protein comprising a polymer binding domain, a target-binding domain, a linker, and a protease cleavage sequence. Popovic discloses an extracellular vesicle binding single-domain antibody for extracellular vesicle capture, and Zhang teaches a fusion protein comprising PHA polymer binding PhaR.
Conclusion
No claims are allowed.
Correspondence Information
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/SANDRA ZINGARELLI/Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653