DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment to the claims, filed September 8, 2026, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Claims 7 and 16-24 are pending in the application.
Applicant’s remarks filed September 8, 2026 in response to the non-final rejection filed July 1, 2026 are acknowledged and have been fully considered.
Claims 10-15 are canceled by applicant’s amendment filed September 8, 2026. The objection and rejections previously applied to claims 10-15 are withdrawn.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Restriction/Election
In response to a requirement for restriction/election filed July 28, 2025, applicant elected without traverse the invention of Group I, corresponding to pending claims 7 and 19-24, species (A-1), and species (D) in the reply filed September 24, 2025.
Claims 16-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 7 and 19-24 are being examined on the merits with claims 7, 20, and 22-24 being examined only to the extent these claims read on the elected subject matter. In the interest of clarity, it is noted that rejections set forth below may be directed to a non-elected species, which has yet to be searched and examined on the merits because the cited prior art was identified during a search and examination of the elected species as set forth above.
Claim Rejections - 35 USC § 103
Claims 7 and 19-24 are rejected under 35 U.S.C. 103 as being unpatentable over Yamaguchi et al. (US 2018/0171364 A1; cited on the IDS filed on October 19, 2022; hereafter “Yamaguchi”) in view of ENDEXT® Technology ProteoLiposome Expression Kit Instruction Manual (CellFree Sciences Co., 2016, 25 pages; cited on the attached Form PTO-892; hereafter “Instruction Manual”).
Claims 7 and 19-24 are drawn to (in relevant part) a lipid membrane structure comprising a protein composition, wherein:
the protein composition comprising protein (B) and protein (A-1):
(A-1) is one or more protein selected from proteins comprising an amino acid sequence of SEQ ID NO: 6 and proteins comprising an amino acid sequence having 90% or more sequence identity with the amino acid sequence of SEQ ID NO: 6 and exhibiting 50% or more of the same isoprene polymerization activity as cis-prenyltransferase 6 (CPTL6); and
(B) is one or more protein selected from proteins comprising an amino acid sequence of SEQ ID NO: 10 and proteins comprising an amino acid sequence having 90% or more sequence identity with the amino acid sequence of SEQ ID NO: 10 and exhibiting 50% or more of the same isoprene polymerization activity as cis-prenyltransferase-like (CPTL);
wherein the structure is a cell-free proteoliposome.
Regarding instant claim 7, Yamaguchi teaches natural rubber is an example of a polyisoprenoid and is obtained by cultivating rubber-producing plants (paragraph [0002]), however, there is concern that natural rubber sources will dry up (paragraph [0003]). Yamaguchi teaches methods for producing a polyisoprenoid by enhancing the rubber synthesis activity of rubber particles or producing a polyisoprenoid by recombinant techniques (paragraphs [0020]-[0021]).
Yamaguchi teaches a “First Invention,” which is a method for producing a polyisoprenoid by binding a protein expressed by a gene coding for a cis-prenyltransferase (CPT) family protein and a protein expressed by a gene coding for a Nogo-B receptor (NgBR) family protein to rubber particles in vitro (paragraph [0062]).
Yamaguchi teaches the rubber particles are derived from the latex of a rubber-producing plant such as Hevea brasiliensis, Taraxacum kok-saghyz, Parthenium argentatum, Sonchus oleraceus, or Ficus elastica. (paragraph [0068]).
Yamaguchi teaches the binding step may be carried out by performing protein synthesis in the presence of both rubber particles and a cell-free protein synthesis solution containing an mRNA coding for the CPT family protein and an mRNA coding for the NgBR family protein to bind the CPT family protein and the NgBR family protein to the rubber particles (paragraph [0233]).
Yamaguchi teaches the cell-free protein synthesis solution preferably contains a germ extract, which is preferably derived from wheat (paragraphs [0037]-[0038]).
Yamaguchi teaches the CPT family protein is particularly preferably derived from Hevea brasiliensis (paragraph [0072]). Yamaguchi teaches the CPT family protein CPT4 from Hevea brasiliensis comprising the amino acid sequence of SEQ ID NO: 37 (paragraphs [0060] and [0738] and Figure 5). SEQ ID NO: 37 of Yamaguchi has greater than 99% sequence identity to instant SEQ ID NO: 6 (see Appendix A of the Office action filed October 29, 2025). Yamaguchi does not explicitly teach CPT4 of SEQ ID NO: 37 exhibits 50% or more of the same isoprene polymerization activity as CPT6. However, since the amino acid sequence of CPT4 of Yamaguchi (i.e., SEQ ID NO: 37 of Yamaguchi) is substantially identical to instant SEQ ID NO: 6, it is presumed that CPT4 of Yamaguchi exhibits 50% or more of the same isoprene polymerization activity as instant CPT6. See MPEP 2112.01.I.
Yamaguchi teaches the NgBR family protein is particularly preferably derived from Hevea brasiliensis (paragraph [0072]). Yamaguchi teaches the NgBR family protein from Hevea brasiliensis (HRTBP) comprising the amino acid sequence of SEQ ID NO: 4 (paragraphs [0187] and [0733]). SEQ ID NO: 4 of Yamaguchi has 100% sequence identity to instant SEQ ID NO: 10 (see Appendix B of the Office action filed October 29, 2025). Yamaguchi does not explicitly teach HRTBP of SEQ ID NO: 4 exhibits 50% or more of the same isoprene polymerization activity as CPTL. However, since the amino acid sequence of HRTBP of Yamaguchi (i.e., SEQ ID NO: 4 of Yamaguchi) is substantially identical to instant SEQ ID NO: 10, it is presumed that HRTBP of Yamaguchi exhibits 50% or more of the same isoprene polymerization activity as instant CPTL. See MPEP 2112.01.I.
Yamaguchi teaches a “Second Invention,” which is a method for producing a polyisoprenoid using a vector comprising a gene coding for a Nogo-B receptor (NgBR) family protein and a gene coding for a cis-prenyltransferase (CPT) family protein (paragraph [0302]; the NgBR family protein and CPT family protein are described by Yamaguchi as noted above).
Yamaguchi teaches introducing the vector of the “second invention” into plant cells or a yeast for production of polyisoprenoid (paragraphs [0339] and [0340]). Yamaguchi teaches that in yeasts and non-rubber-producing plants, the products synthesized by the CPT family proteins transfer from the hydrophobic cleft structures of the CPT family proteins into the lipid bilayers of cells and accumulate in the lipid bilayers (paragraphs [0182] and [0183]). Yamaguchi teaches NgBR family proteins bind to a membrane via one or more transmembrane domains and interact with the CPT family protein (paragraph [0186]).
Yamaguchi does not explicitly teach a cell-free proteoliposome.
While Yamaguchi’s “First Invention” involves the use of rubber particles derived from the latex of a rubber-producing plant (paragraphs [0062] and [0068]), one of ordinary skill in the art would have recognized a shortcoming of Yamaguchi’s “First Invention” is the requirement for rubber particles derived from the latex of a rubber-producing plant as Yamaguchi’s own disclosure acknowledges the concern that natural rubber sources will dry up (paragraph [0003]).
Also, while Yamaguchi’s “Second Invention” involves the use of a plant or yeast cell as an expression host to accumulate the NgBR family protein and the CPT family protein, which are membrane proteins, into the lipid bilayer (paragraphs [0182], [0183], [0185], and [0186]), one of ordinary skill in the art would have recognized a shortcoming of Yamaguchi’s “Second Invention” in view of Instruction Manual, which teaches that expression of eukaryotic membrane proteins presents challenges caused by complications to express those proteins in standard protein expression systems, where membrane proteins can be toxic to cell system used or form insoluble aggregates (p. 2, top).
Instruction Manual teaches these problems can be addressed by using the wheat germ cell-free protein expression system offered by CellFree Sciences. According to Instruction Manual, by adding liposomes to the translation reaction, membrane proteins are directly inserted into the lipid bilayer of the liposome to form proteoliposome complexes (p. 2, top). Instruction Manual teaches a kit that provides all necessary reagents to prepare proteoliposome complexes for proteins of interest and the proteoliposomes can be easily isolated by centrifugation (p. 2, top).
In view of the combined teachings of Yamaguchi and Instruction Manual, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify Yamaguchi to make a cell-free proteoliposome comprising the CPT family protein and the NgBR family protein. One would have been motivated to do this because one of ordinary skill in the art would have recognized shortcomings of Yamaguchi’s “First Invention” and “Second Invention,” while Instruction Manual teaches cell-free production of membrane proteins with liposomes to form a proteoliposome complex, which does not suffer from the shortcomings of using natural rubber particles and standard cell-based protein expression systems of Yamaguchi’s “First Invention” and “Second Invention.” One would have had a reasonable expectation of success because Instruction Manual taught a kit that provides all necessary reagents to prepare proteoliposome complexes for proteins of interest and taught the proteoliposomes can be easily isolated.
Regarding instant claim 19, Yamaguchi acknowledges that lipid bilayer membranes are formed of phospholipids (paragraph [0236]).
Regarding instant claim 20, given that there are only three amino acid differences between SEQ ID NO: 37 of Yamaguchi and instant SEQ ID NO: 6 (see Appendix A of the Office action filed October 29, 2025) and given the degeneracy of the genetic code, SEQ ID NO: 37 of Yamaguchi is necessarily encoded by a polynucleotide comprising a nucleic acid sequence having 90% or more sequence identity with the nucleic acid sequence of SEQ ID NO: 5.
Regarding instant claims 21 and 22, Yamaguchi teaches the CPT family protein and NgBR family protein bind to rubber particles and produce a polyisoprenoid (paragraph [0050]). Yamaguchi teaches that binding the CPT family protein and NgBR family protein to rubber particles is expected to stabilize and increase the activity of the CPT family protein (paragraph [0050]). Yamaguchi teaches that in the binding step, other proteins may further be bound to the rubber particles (paragraph [0229]), which are preferably proteins that inherently exist on rubber particles in rubber-producing plants (paragraph [0231]), which are exemplified by rubber elongation factor (REF) and small rubber particle protein (SRPP) (paragraph [0232]). Yamaguchi teaches REF is encoded by the nucleotide sequence of SEQ ID NO:27 (paragraph [0440]). SEQ ID NO: 27 of Yamaguchi has 100% sequence identity to instant SEQ ID NO: 13 (see Appendix D of the Office action filed October 29, 2025). Yamaguchi does not explicitly teach REF of SEQ ID NO: 27 exhibits 50% or more of the same isoprene polymerization activity as REF2. However, since the amino acid sequence of REF of Yamaguchi (i.e., SEQ ID NO: 27 of Yamaguchi) is substantially identical to instant SEQ ID NO: 13, it is presumed that REF of Yamaguchi exhibits 50% or more of the same isoprene polymerization activity as instant REF2. See MPEP 2112.01.I.
Regarding instant claim 23, given that SEQ ID NO: 28 of Yamaguchi is identical to instant SEQ ID NO: 14 (see Appendix C of the Office action filed October 29, 2025), and given the degeneracy of the genetic code, SEQ ID NO: 28 of Yamaguchi is necessarily encoded by a polynucleotide comprising a nucleic acid sequence having 90% or more sequence identity with the nucleic acid sequence of SEQ ID NO: 13.
Regarding instant claim 24, Yamaguchi teaches Hevea brasiliensis is para rubber tree (paragraph [0002]) and teaches the REF of SEQ ID NO: 28, which is from Hevea brasiliensis (paragraph [0736]).
Therefore, the invention of claims 7 and 19-24 would have been obvious to one of ordinary skill in the art before the effective filing date.
RESPONSE TO REMARKS: Applicant argues one of ordinary skill in the art would understand that the rubber particle is critical and essential to Yamaguchi’s “First Invention.” Applicant further argues that because rubber particles possess a monolayered membrane, while liposomes of Instruction Manual have a bilayered membrane, modifying Yamaguchi to make a cell-free proteoliposome comprising the CPT family protein and the NgBR family proteins would fundamentally destroy Yamaguchi’s principle of operation.
Applicant’s arguments are not found persuasive. Yamaguchi’s teachings are not limited to a “First Invention.” Rather, as stated above, Yamaguchi teaches a “First Invention” and a “Second Invention.” Yamaguchi teaches the “Second Invention” involves accumulation of the CPT family proteins into lipid bilayers (paragraphs [0182] and [0183]), which is same principle as Instruction Manual (p. 3, Figure 1), however, membrane protein expression into the lipid bilayer of liposomes as taught by Instruction Manual does not suffer from the problems of cell-based expression of membrane proteins of Yamaguchi’s “Second Invention.”
Applicant further argues there is no suggestion in Yamaguchi to abandon the natural rubber particle of the “First Invention” and the cell-based expression system of the “Second Invention” in favor of the liposomes of Instruction Manual.
Applicant’s arguments are not found persuasive. As stated above, one of ordinary skill in the art would have recognized that Yamaguchi’s “First Invention” and “Second Invention” suffer from the requirements for natural rubber particles and cell-based protein expression of membrane proteins, respectively. One of ordinary skill in the art would have recognized that cell-free production according to Instruction Manual does not require the use of natural rubber particles and/or a cell-based protein expression system and would have been motivated to combine Yamaguchi and Instruction Manual to modify Yamaguchi to make a cell-free proteoliposome comprising the CPT family protein and the NgBR family protein.
Applicant further argues that it would have been difficult for one of ordinary skill to replace the rubber particles in Yamaguchi with the liposomes of Instruction Manual because of the different environments, which affect the rubber chain extension, and because liposomes have an aqueous solution core that is not hydrophobic.
Applicant’s arguments are not found persuasive. Yamaguchi teaches the “Second Invention” involves accumulation of the CPT family proteins into lipid bilayers (paragraphs [0182] and [0183]), which is same principle as Instruction Manual (p. 3, Figure 1) and Instruction Manual taught a kit that provides all necessary reagents to prepare proteoliposome complexes for proteins of interest and taught the proteoliposomes can be easily isolated. As such, one would have had a reasonable expectation of success to modify Yamaguchi to make a cell-free proteoliposome comprising the CPT family protein and the NgBR family protein.
For these reasons, it is the examiner’s position that the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Status of the claims:
Claims 7 and 16-24 are pending in the application.
Claims 16-18 are withdrawn from consideration.
Claims 7 and 19-24 are rejected.
No claim is in condition for allowance.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID J STEADMAN whose telephone number is (571)272-0942. The examiner can normally be reached Monday to Friday, 7:30 AM to 4:00 PM.
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/David Steadman/Primary Examiner, Art Unit 1656
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