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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/26/2025 has been entered.
Response to Amendment
The amendment filed 08/26/2025, amending claim(s) 1, 3, 6-8, 11, 15, 25, 28, 30, 33, 36, cancelling claim(s) 2, 10, 16, 18, 19, 22, 24, 26, 29, 35, 38-42, and newly adding claims 43-46 is acknowledged.
Claim 43 is withdrawn due to being drawn to a non-elected species (anti-microbial) (immunomodulatory protein was elected in the response filed 10/10/2024.
Claims 1, 3-9, 11-15, 17, 20, 21, 23, 25, 27, 28, 30-34, 36-38, 40, 41 are pending.
Claims 1, 3-5, 12-15, 25, 27, 28, and 44-46 are pending and under examination.
The amendment to the claims filed on 08/26/2025 does not comply with the requirements of 37 CFR 1.121(c). Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
The correct status identifier for claim 11 is (Withdrawn- Currently Amended).
The correct status identifier for claim 43 is (Withdrawn- New).
Priority
Applicant’s claim for the benefit of a prior-filed application PCT/US2018/019763 filed 04/01/2020 and provisional application 62/827,772 filed on 04/01/2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. The effective filing date of the claims is granted as the filing date of provisional application 62/827,772 filed on 04/01/2019.
Specification
The amended specification was received on 04/21/2025. The specification is acceptable.
Claim Interpretation
Newly amended claim 1 recites “wherein the one or more exogenous secreted proteins or functional fragments thereof are inserted into one or more endogenous genes of the cell, wherein the one or more endogenous genes encode the one or more exogenous secreted proteins or functional fragments”. The Examiner interprets this recitation to read on the insertion of one or more secreted proteins into one or more endogenous genes, where the endogenous genes encode a secretory protein or peptide that may be the same or different from the inserted secreted protein.
Claim Rejections - 35 USC § 112(a) – New, necessitated by amendment
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, 3-5, 12-15, 25, 27, 28, and 44-46 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.
Newly amended claim 1 recites “a functional fragment of any of the foregoing that retains at least 20% biological activity of a wild-type protein”. “Thereof” is interpreted as referring back to exogenous secreted proteins.
The exogenous secreted protein may be an immunomodulatory protein (claim 3).
The exogenous secreted protein may be a cytokine (claim 4).
The exogenous secreted protein may be IL-10 (claim 5).
The engineered cell may be a eukaryotic cell (claim 12).
The engineered cell may be a human cell (claim 13).
The engineered cell may be a beta cell (species previously elected for examination) (claim 14).
The engineered cell may be a pancreatic cell (claim 15).
The engineered cell may be a pancreatic cell that is a beta cell differentiated from a progenitor in vitro (claim 44).
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The exogenous secreted protein(s) in the claimed engineered cell are recited at a high level of generality, specifically the recitation of “a functional fragment of any of the foregoing that retains at least 20% biological activity of a wild-type protein”.
The specification indicates that:
“functional fragment means that the sequence of the polypeptide may include less amino-acid than the original sequence but still enough amino-acids to confer the enzymatic activity of the full-length protein. A “functional fragment” may substantially retains at least one biological activity normally associated with that protein. In some examples, a functional fragment substantially retains all of the activities possessed by the full-length protein. By "substantially retains" biological activity, it is meant that the fragment retains at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 75%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, of the biological activity of the full-length protein. Small peptides from plant/animal origins with similar biological activity as a protein or functional fragment are also contemplated for use herein” [0067].
Thus, “functional fragment” is a functional limitation of the claimed secretory proteins. In addition, a search of the specification returned reiterations of the claim language (e.g., [0005]; [0100] on pg. 10; statement 1 on pg. 76). The specification does not teach how the secretory proteins can be modified and still maintain the same function. For example, what is the 20% biological activity that must be retained? How would an artisan define this “biological activity” and know that at least 20% is retained? Does this “biological activity” differ from protein to protein? What “function” must the fragment have?
Further, the working examples of the specification teach few examples of inserting exogenous secreted proteins. In one proof of concept, HiBiT was knocked-in at the c-peptide portion of the INS1 locus in INS-1E cells [0286]. INS1e cells were also engineered using Cas9 to secrete IL-10, where IL-10 was inserted into the c-peptide region to allow for co-secretion of the gene product (IL-10) with insulin.
The claim is considered to lack adequate written description for failing to recite the structure that is necessary and sufficient to cause the recited functional language (i.e., retaining at least 20% biological activity). The specification fails to disclose what structural changes to the exogenous secreted protein(s) is/are necessary and sufficient to produce engineered cells sharing the same functional properties (e.g., what fragment of a secretory protein would/would not result in a function a functional fragment?), and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg. 63, col. 1), which in this case, would affect the ability of the genus of structurally undisclosed secretory protein variants so as to necessarily and predictably maintain the recited biological functional property(ies) of the corresponding protein.
Ng et al taught that while multiple sequence alignment of the homologous sequences reveals what positions have been conserved throughout evolutionary time, and these positions are inferred to be important for function (e.g. pg. 63, col. 1), Users should be cautious even with proteins that are judged to be orthologous based on phylogeny. Orthologous genes in different species are derived from a common ancestor, but they may not necessarily have the same function. If function has changed, then amino acids that are important for the function of one protein may not necessarily be important for the function of the ortholog. 2% of disease-causing mutations in human genes are identical to the sequences of their respective mouse orthologs, suggesting that even though these positions have huge phenotypic effects on human health, they have different roles or are no longer important in mice If the orthologs in alignment have slightly different functions, then the positions that differentiate function among orthologs may be incorrectly predicted. (e.g. pg. 68, col. 1). When there are many missense mutations in the gene(s) of interest, assaying all missense mutations, which introduce amino acid changes, can be expensive and time-consuming (e.g. pg. 74, col. 1). Prediction accuracy has gradually improved, but few head-to-head comparisons exist. Moreover, as the number of servers providing AAS prediction increases, it will become increasingly difficult for investigators to interpret the predictions. (e.g. pg. 74, col. 2). Ng et al taught that the error rate of functional annotations in the sequence database is considerable, making it even more difficult to infer correct function from a structural comparison of a new sequence with a sequence database (e.g. Table 1, error rates of about 40% to 60%).
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.
Consequently, the gap between the number of as-yet to be discovered protein sequences of the claimed, but not structurally disclosed, genus of peptide variants is considered to be tremendous, notoriously difficult, slow, very laborious and time-consuming for the ordinary artisans to determine for themselves that which Applicant has failed to disclose.
Given the extremely large and structurally diverse genus of secretory protein “fragments”, the lack of working examples in the specification of secretory protein fragments, and in view of Ng et al., the skilled artisan would conclude that Applicant did not possess the genus of secretory protein fragments that retain biological activity as claimed.
Additionally, claim 1 recites “an exogenous co-expressed protein that enhances the expression, stability or biological activity of the one or more exogenous secreted proteins”. The exogenous co-expressed protein of the claimed engineered cell is recited at a high level of generality.
The claim is considered to lack adequate written description for failing to recite the structure that is necessary and sufficient to cause the recited functional language (i.e., enhances the expression, stability or biological activity). The claim limitations recited above merely state functional characteristics without providing any indication about how the functional characteristic is provided.
The specification fails to disclose what structures of the co-expressed protein in the claimed engineered cell is necessary and sufficient to cause the recited functions, and thus the ordinary artisan would not know what modification(s) must be made or what structure must be present in order to fulfill the instant recitation. For example, how would an artisan know whether a co-expressed protein will enhance the expression, stability or biological activity of the one or more exogenous secreted proteins? A search of the specification for “co-express[ed]” only returned re-iterations of the claim language and the following related to anti-fibrillating polypeptides:
[0092] The polynucleotide may encode an anti-fibrillating polypeptide. The anti- fibrillating polypeptide can be the secreted polypeptide. In some aspects the anti-fibrillating polypeptide is co-expressed with one or more other polynucleotides and/or polypeptides described elsewhere herein. The anti-fibrillating agent can be secreted and act to inhibit the fibrillation and/or aggregation of endogenous proteins and/or exogenous proteins that it may be co-expressed with.
The claims fail to recite, and the specification fails to disclose, the structure/function nexus between the genus of co-expressed proteins and the functional properties of enhancing the expression, stability or biological activity of the secreted protein.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 112(b) – New, necessitated by amendment
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 46 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 46 recites “wherein the one or more polynucleotides comprise a protease cleavage site on each end”. It is unclear how a nucleic acid can comprise a protein sequence, as nucleic acids encode proteins. It would be remedial to amend the claim to recite that the one or more polynucleotides encode a protease cleavage site on each end. For examination purposes, prior art teaching the one or more polynucleotides encoding a protease cleavage site on each end is interpreted to read upon the claim limitations.
Claim Rejections - 35 USC § 102 - Maintained
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3, 12-15, 25, 28, and 44-46 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Minnesota (WO2017023803A1, published February 9th, 2017; included in IDS).
Regarding claim 1, Minnesota discloses an engineered cell (i.e., genetically modified immune cell) (Abstract) comprising one or more polynucleotides encoding:
one or more exogenous secreted proteins, such as a T cell receptor (TCR) sequence, inserted into an endogenous gene (e.g., an endogenous immune checkpoint gene) [0008], [0009], [0050], [0355], [00360], [00361]
An exogenous co-expressed protein, such as an enhancer or nuclease, that enhances the expression, stability or biological activity of the secreted protein [0050]- pg. 16, [00359], [0363], [00364]
Regarding claim 3, Minnesota discloses the secretory protein being an modulatory protein (e.g., TCR)
Regarding claims 12 and 13¸ Minnesota discloses the cell being a human (i.e., eukaryotic) cell [00170].
Regarding claims 14 and 15, Minnesota discloses the engineered cell being a pancreatic beta cell [00303].
Regarding claims 25 and 45, Minnesota discloses the cell further comprising one or more polynucleotides encoding interference RNA, including siRNA [0269], [0277].
Claim Rejections - 35 USC § 102/103 – New, necessitated by amendment
Claim(s) 28, 44, and 46 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Minnesota, evidenced by Chmielowiec (Chmielowiec, Jolanta, and Malgorzata Borowiak. “In vitro differentiation and expansion of human pluripotent stem cell-derived pancreatic progenitors.” The review of diabetic studies : RDS vol. 11,1 (2014): 19-34. doi:10.1900/RDS.2014.11.19.).
Regarding claims 28 and 46, Minnesota discloses that a nucleic acid may comprise one or more restriction sites (and also the exogenous secretory protein as part of intracellular genomic transplant), wherein cleaving the nucleic acid at the restriction site fragments the nucleic acid, and that a restriction site may generally refer to a specific peptide or nucleotide sequences at which site-specific molecules (e.g., proteases, endonucleases, or enzymes) may cut the nucleic acid (e.g., also considered a protease cleavage site according to [0093] and [0094] of instant specification) [00244]. In one example, the nucleic acid may comprise a restriction site, wherein digesting the nucleic acid at the restriction site with a restriction enzyme (e.g., Notl) produces a 4 nucleotide overhang. In some cases, the modifying comprises generating a blunt end at one or more ends of the nucleic acid (i.e., reads on “on each end”) [00245]. Therefore, based on the disclosure of Minnesota, an artisan could reasonably arrive at the claimed invention.
Regarding claim 44, Minnesota discloses that the cell may be a pancreatic beta cell, as well as a differentiated progenitor cell (which reads on a pancreatic beta cell differentiated from a progenitor cell) [0007], [0021], [00303], [00304], [00306], [00309].
Minnesota does not explicitly state that the cells may be differentiated in vitro. However, techniques to differentiate cells from progenitors cells in vitro are well known and routine in the art, as evidenced by Chmielowiec (e.g., Abstract). Absent evidence to the contrary, the cells taught by Minnesota may be differentiated in vitro, and one of ordinary skill in the art could reasonably arrive at the claimed invention based on the disclosure of Minnesota.
Claim Rejections - 35 USC § 103 – New, necessitated by amendment
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 4, 5, and 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Minnesota as applied to claims 1, 3, 12-15, 25, 28, and 44-46 above, and further in view of Juno.
The Artisan, interested in methods to engineer cell to comprise an exogenous secretory protein in an endogenous gene, would be aware of Juno for teaching another example of such cells.
Juno teaches an engineered cell (i.e., engineered B cell) (Abstract) comprising one or more polynucleotides encoding: one or more secreted proteins, or a functional fragment thereof, wherein the one or more secreted proteins or functional fragments thereof are inserted in one or more endogenous genes of the cell, the one or more endogenous genes encoding a secretory protein or peptide (claims 7-9 of Juno).
Regarding claims 4 and 5, Minnesota does not teach the immunomodulatory protein being a cytokine or IL-10.
Juno teaches the immunomodulatory protein being IL-2, IL-4, IL-6, IL-10, IL-15, or IL-22 (claim 19 of Juno) [0165].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the cytokine taught by Minnesota with the cytokine IL-10 taught by Juno with a reasonable expectation for success. An artisan would have a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re
Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” M.P.E.P. §2144.06.
Further, replacing a cytokine with another has long been done in the molecular biology art and would be routine. One would be motivated to replace the cytokine taught by Minnesota because as taught by Juno, IL-10 can be used to modulate B cell differentiation and stimulate cells [0069, 0305].
Regarding claim 27, Minnesota and Juno do not explicitly do not teach the engineered cell further comprising one or more polynucleotides encoding interference RNA that suppresses TGF-beta, colony-stimulating factor 1, or a combination thereof.
Minnesota does teach the cell further comprising one or more polynucleotides encoding interference RNA.
Juno teaches the engineered cell further comprising one or more polynucleotides encoding interference RNA, optionally wherein the interference RNA is siRNA [0256; 0261-0268].
Juno teaches achieving gene repression using antisense techniques, such as by RNA interference (RNAi) to selectively suppress or repress expression of a gene [0387; 0439-440]. Additionally, Juno teaches the engineered cell comprising a recombinant receptor comprising a ligand binding domain (claim 7 of Juno) Juno teaches that this ligand may be a colony stimulatory factor (CSF) or TGF-beta [0229; 0234]. Juno also teaches the signal sequence in the engineered cell comprising TGF-beta [0195]. Additionally, Juno teaches TGF-beta and/or CSF being a stimulating agent or growth factor for the engineered cell [0162; 0303, 0305]. While Juno does not explicitly disclose the RNAi suppressing TGF-beta, CSF-1, or a combination thereof, Juno does teach using RNAi to repress a variety of genes, such as OCT2 and ETS1 [0261-0268]. Additionally, Juno teaches that gene repression achieved using RNAi is known in the art [0387; 0439].
Therefore, at the time of effective filing of the instant case, an artisan would have known that one can use RNAi to suppress the expression of a gene of their choice. One would be motivated to use RNAi for gene suppression because as taught by Juno, RNAi can selectively suppress or repress expression of a targeted gene [0439-0441].
Further, it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the engineered cell taught by Minnesota by Juno to suppress the recited genes and yield predicable results. Adding the RNAi taught by Juno would not alter the co-expression of a protein that enhances the biological activity of the secreted protein. Juno teaches that gene repression via RNAi is known in the art [0387]. One would be motivated to add the RNAi to the engineered cell of Minnesota because as taught by Juno, RNAi can be used to selectively suppress or repress expression of a gene [0439].
Response to Arguments
Applicant's arguments filed 08/26/2025 have been fully considered but they are not persuasive.
Regarding the 112(a) written description rejection, specifying "exogenous secreted proteins" and "exogenous co-expressed protein," to explicitly define functional fragments as those "that retain at least 20% of the biological activity of the full-length protein" does not further clarify the relationship between the endogenous genes and exogenous proteins, nor further limit the structure of the proteins.
The applicant argues:
“the Office's characterization of "functional fragments" as an "enormously vast genus" ignores the claim's explicit limitation to five enumerated protein categories: immunomodulatory proteins, anti-fibrotic proteins, hormones, anti-microbial proteins, and tissue regeneration proteins.
The specification provides clear constraints requiring functional fragments to retain substantial biological activity and must include sufficient amino acids to confer the enzymatic activity of the full-length protein. As now explicitly recited in the amended claim, functional fragments must "retain at least 20% of the biological activity of the full-length protein," a quantitative parameter that establishes a clear boundary for the claimed genus. The specification at paragraph [0067] provides detailed guidance on the biological activity requirements for functional fragments, establishing a range from at least 20% up to at least 99% of the biological activity of the full-length protein.”
“The specification provides support for each claimed exogenous protein category, including immunomodulatory proteins (paragraphs [0074]-[0081]), anti-fibrotic proteins (paragraph [0082]), hormones (paragraphs [0084]-[0086]), anti-microbial proteins (paragraph [0087]), and tissue regeneration proteins (paragraph [0083]), as specifically enumerated in the amended claims.
The specification provides guidance regarding functional fragments and their relationship to the parent proteins at paragraph [0067], which explicitly defines functional fragments as those retaining at least 20% of the biological activity of the full-length protein-now incorporated directly into the claim language. This creates clear boundaries that guide skilled artisans to the claimed invention.
The exogenous co-expressed protein limitation requires a specific, testable functional relationship - that the co-expressed protein must "enhance the expression, stability or biological activity of the exogenous secreted protein." This creates definite, measurable criteria that distinguish this limitation from purely functional claiming rejected in Eli Lilly.”
The arguments are not found to be persuasive. Firstly, the five enumerated protein categories recited are in themselves are broad. For example, over 20 years ago in 2005, the Encyclopedic Reference of Immunotoxicity noted that about 200 cytokines had been identified (pg. 181, “Classification of Cytokines”). Cytokines are just one species in the immunomodulatory protein genus, one of the five protein categories claimed.
Additionally, as discussed in the 112(a) rejection above, [0067] does not provide the artisan enough information to determine the scope of the functional fragment(s) "retain[ing] at least 20% of the biological activity of the full-length protein". The working examples of the specification also do not provide further guidance.
In addition, the functional relationship between the exogenous secreted protein and co-expressed exogenous protein also does not clearly define/limit the structure(s) of the protein(s). How would one measure this criteria? What structure leads to this function? What modification(s) to the protein(s) would still result in this function? Limiting the co-expressed exogenous protein functionally does not provide clear guidance for an artisan on what proteins are included in this genus, nor provide evidence of possessing the claimed cell.
Regarding the Applicant’s argument concerning Ng et al., while the modifications discussed by Ng et al. are related to disease-causing mutations, the teachings of Ng are still relevant and applicable. Ng et al. is referenced to teach how modifying the structure of a nucleic acid or polypeptide can change the function of the resulting protein. Regardless of how or why the modifications take place, Ng et al. teaches that an artisan cannot readily predict or know how to modify the structure (e.g., how to select a functional fragment) of the genera of proteins in the claims yet still maintain the desired function without consequences. Additionally, the Applicant argues that Ng et al. is misplaced compared to the “engineered” functional fragments of the claimed invention. However, there is nothing in the claim language that speaks to or requires the sequence of the fragment(s) to be engineered in a deliberate way. Defining the fragments by function does not tell an artisan what structure to engineer, still reads on fragments that may comprise modifications resulting from a mutation, for example.
Regarding the teachings of Minnesota, The Applicant argues:
“[00196] and the entire Minnesota reference reveals that Minnesota does not disclose "exogenous secreted proteins" as required by amended claim 1. Paragraph [00196] of Minnesota merely states "One or more cytokines can be introduced with cells of the invention." This language describes cytokines being provided alongside cells (i.e., co- administration of cytokines with cells), not genetically modifying cells to express exogenous secreted proteins. There is a fundamental difference between (1) providing external cytokines alongside cells as described in Minnesota, and (2) engineering cells with polynucleotides encoding exogenous secreted proteins that are inserted into endogenous genes as claimed in the present application.”.
This argument is found to be persuasive. However, the disclosure of Minnesota, as discussed above, still teaches the claimed invention.
Additionally, the Applicant argues:
“The Office cites paragraphs [0008, 0009, 00366, 00370] of Minnesota as allegedly disclosing "a co-expressed protein that enhances the expression, stability, or biological activity of the secreted protein." Even if Minnesota's HR enhancers (E1B55K, E4orf6, Scr7, or L755507) could be considered "co-expressed proteins" (which Applicant does not concede), Minnesota fails to disclose that these HR enhancers are encoded by polynucleotides alongside exogenous secreted proteins.
Additionally, Minnesota fails to disclose that these proteins are exogenous or that they enhance exogenous secreted proteins. Minnesota's HR enhancers are disclosed exclusively for enhancing DNA repair during gene editing, not for improving the properties of secreted proteins. Furthermore, there is no teaching that these HR enhancers are exogenous proteins that remain expressed in the final engineered cell.”
These arguments are not found to be persuasive. Minnesota teaches these enhancers and other proteins, such as endonucleases, as being exogenous (e.g., claim 4 of Minnesota). These enhancers and endonucleases are also taught to assisted the exogenous secreted protein (e.g., claim 30 of Minnesota, [0050])/aid in the introduction of the exogenous secreted protein to the cell’s genome, thus enhancing the expression, stability, or biological activity of the secreted protein. Additionally, Minnesota teaches that a transgene may comprise a promoter and/or enhancer, for example a constitutive promoter or an inducible or tissue/cell specific promoter [00359], and that “exogenous sequences may also include transcriptional or translational regulatory sequences, for example, promoters, enhancers, insulators, internal ribosome entry sites, sequences encoding 2A peptides and/or polyadenylation signals.” [00363] (e.g., a exogenous secreted protein and exogenous co-expressed protein together).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638