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 .
Detailed Action
This action is in response to the papers filed September 15, 2025.
Amendments
Claims 1-9, 11-12, 15-18, 20-21, and 24-26 are pending.
Election/Restrictions
Applicant has elected without traverse the following species:
i) the alternative first and second antigens, respectively, of target antigen pair, is EGFR and MET;
ii) the alternative first and second transcription factors, respectively, of the gene circuit, is GAL4 and LexA, as recited in Claim 3;
iii) the alternative first and second binding-triggered transcriptional switch receptor that undergoes binding-induced proteolytic cleavage, respectively, of the gene circuit, is synNotch, as recited in Claim 5;
iv) the alternative therapeutic protein is a chimeric antigen receptor (CAR), as recited in Claim 8-9; and
v) the alternative cell is an immune cell, as recited in Claim 21.
Claims 1-9, 11-12, 15-18, 20-21, and 24-26 are pending.
Claims 11-12, 15-18, and 24 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1-9, 20-21, and 25-26 are under consideration.
Priority
This application is a 371 of PCT/US2021/18780 filed on February 19, 2021. Applicant’s claim for the benefit of a prior-filed application provisional application 62/980,889, filed on February 24, 2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on August 18, 2022 that has been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.
The Examiner cites below Applicant's own prior art, not cited in an IDS, to wit:
Lim et al (WO 17/193059; and
Roybal et al (Precision Tumor Recognition by T Cells With Combinatorial Antigen-Sensing Circuits, Cell 164: 770-779, 2016).
Applicant is reminded of their duty to disclose information material to patentability. See MPEP §2001 and 37 C.F.R. 1.56.
The individuals covered by 37 CFR 1.56 have a duty to bring to the attention of the examiner, or other Office official involved with the examination of a particular application, information within their knowledge as to other copending United States applications which are "material to patentability" of the application in question. As set forth by the court in Armour & Co. v. Swift & Co., 466 F.2d 767, 779, 175 USPQ 70, 79 (7th Cir. 1972):
[W]e think that it is unfair to the busy examiner, no matter how diligent and well informed he may be, to assume that he retains details of every pending file in his mind when he is reviewing a particular application . . . [T]he applicant has the burden of presenting the examiner with a complete and accurate record to support the allowance of letters patent.
See MPEP §2001.06(b).
Pursuant to the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.), a copy of the Applicant's own publication(s) are not provided with the instant Office Action because it is presumed that Applicant has a copy of their own publications, as such is routine practice in the art, and that Applicant has provided their representative with a copy of said publications to establish a prosecution record. However, if Applicant’s representative insists upon receiving a copy of the entire references, then the Examiner will make attempts to provide it in the next Office Action.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
1. Claim 20 is objected to because of the following informalities: Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
Embodiments (i), (ii), and (iii) should be separated by line indentation.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
2. Claim(s) 1-9 and 20-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites a first expression cassette comprising a promoter and a first coding sequence encoding a BTTS that binds an antigen on a diseased cell and a first transcription factor;
a second expression cassette comprising a second promoter, a binding site for the first transcription factor, and a second coding sequence encoding a second BTTS that binds a second antigen on a diseased cell and a second transcription factor; and
a third expression cassette comprising a third promoter, a binding site for the second transcription factor, and a third coding sequence encoding a therapeutic protein.
The first, second, and third promoters are each recited at a high level of generality.
The first and second BTTS are each recited at a high level of generality.
The first and second transcription factors are each recited at a high level of generality.
The first and second transcription factor binding sites are each recited at a high level of generality.
The therapeutic protein is recited at a high level of generality.
Claim 2 recites wherein the first transcription factor of (a)(ii) [structure 1] activates transcription of the second promoter more than [function 1] the second transcription factor of (b)(ii) [structure 2] activates transcription of the third promoter [function 2].
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 recitation (a) “more than” (b) is a result-effective variable dependent upon several parameters, including, but not limited to:
i) the structure of the first antigen and its binding affinity to the first BTTS;
ii) the amount of the first antigen present on the target cell;
iii) the structure of the first transcription factor;
iv) the structure of the second promoter;
v) the structure of the second antigen and its binding affinity to the second BTTS;
vi) the amount of the second antigen present on the target cell;
vii) the structure of the second transcription factor; and
viii) the structure of the third promoter.
With respect to the first, second and third promoters, recited at a high level of generality,
Maston et al (Transcriptional Regulatory Elements in the Human Genome, Ann. Rev. Genomics Hum. Genet. 7:29-59, 2006) is considered relevant prior art for having taught that proximal promoters may be as long as 1000 nucleotides (e.g. Figure 1).
4^100 = 1x10^60 structurally and functionally undisclosed nucleic acid sequences that are to have promoter activity.
4^250 = 3x10^150 structurally and functionally undisclosed nucleic acid sequences that are to have promoter activity.
4^500 = 1x10^301 structurally and functionally undisclosed nucleic acid sequences that are to have promoter activity.
4^750 = an infinite genus of structurally and functionally undisclosed nucleic acid sequences that are to have promoter activity.
4^1000 = an infinite genus of structurally and functionally undisclosed nucleic acid sequences that are to have promoter activity.
(www.calculator.net/exponent-calculator; last visited June 25, 2025)
Thus, instant claims reasonably encompass an essentially infinite and/or enormously vast genus of about 1x10^301, 1x10^150, and/or 1x10^60 structurally and functionally undisclosed nucleic acid sequences that are to have a “second” promoter activity and a “third” promoter activity, respectively.
With respect to the first and second transcription factors, recited at a high level of generality, that are to bind to the second and third promoters, respectively, there are about 1600 known transcription factors just in the human genome (Wikipedia, Transcription factor; en.wikipedia.org/wiki/Transcription_factor; last visited May 30, 2025).
Tiessen et al (Mathematical modeling and comparison of protein size distribution in different plant, animal, fungal and microbial species…, BioMedCentral Research Notes 5: e85, 23 pages, doi.org/10.1186/1756-0500-5-85; 2012) is considered relevant prior art for having taught that the average eukaryotic protein is about 470 amino acids in length (Abstract).
20^125 = about 4x10^162 structurally and functionally undisclosed proteins.
20^175 = about 4x10^227 structurally and functionally undisclosed proteins.
20^225 = about 5x10^292 structurally and functionally undisclosed proteins.
20^275 = an infinite genus of structurally and functionally undisclosed proteins.
It is axiomatic that 20^325, 20^375, 20^425, 20^470 each are also an infinite genus of structurally and functionally undisclosed proteins.
Thus, instant claims reasonably encompass:
an essentially infinite and/or enormously vast genus of about 5x10^292, 4x10^227, and/or 4x10^162 structurally and functionally undisclosed amino acid sequences that are to have the functional properties of being a transcriptional activator upon binding to an essentially infinite and/or enormously vast genus of about 1x10^301, 1x10^150, and/or 1x10^60 structurally and functionally undisclosed “second” promoter nucleic acid sequences; and
an essentially infinite and/or enormously vast genus of about 5x10^292, 4x10^227, and/or 4x10^162 structurally and functionally undisclosed amino acid sequences that are to have the functional properties of being a transcriptional activator upon binding to an essentially infinite and/or enormously vast genus of about 1x10^301, 1x10^150, and/or 1x10^60 structurally and functionally undisclosed “third” promoter nucleic acid sequences,
whereby the transcriptional activity of the first transcription factor is to be greater than the transcriptional activity of the second transcription factor.
With respect to the first and second transcription factor binding sites, recited at a high level of generality,
similar to the proximal promoters, such binding sites may be as long as 1000 nucleotides, and thus instant claims reasonably encompass an essentially infinite and/or enormously vast genus of about 1x10^301, 1x10^150, and/or 1x10^60 structurally and functionally undisclosed nucleic acid sequences that are to have the functional properties of binding to a first or second transcription factor of an essentially infinite and/or enormously vast genus of about 5x10^292, 4x10^227, and/or 4x10^162 structurally and functionally undisclosed amino acid sequences that are to have the functional properties of being a transcriptional activator.
With respect to the first and second antigens, recited at a high level of generality,
Blair et al (U.S. 20240067985) disclosed wherein the antigen may be as many as 8 to 35 amino acids in length (e.g. [0022]), or as many as 40 amino acids in length (e.g. [0023]).
20^35 = 3x10^45 structurally undisclosed peptides.
20^40 = 1x10^52 structurally undisclosed peptides.
(www.calculator.net/exponent-calculator; last visited June 25, 2025)
Thus, instant claims reasonably encompass an enormously vast genus of about 1x10^52, and/or 3x10^45 structurally and functionally undisclosed amino acid sequences that are to be bound by the first and second BTTS, respectively.
With respect to the first and second BTTS comprising an extracellular binding domain, recited at a high level of generality,
As discussed above, the average eukaryotic protein is about 470 amino acids in length.
20^25 = about 3x10^32 structurally and functionally undisclosed proteins.
20^50 = about 1x10^65 structurally and functionally undisclosed proteins.
20^75 = about 3x10^97 structurally and functionally undisclosed proteins.
20^100 = about 1x10^130 structurally and functionally undisclosed proteins.
20^125 = about 4x10^162 structurally and functionally undisclosed proteins.
20^175 = about 4x10^227 structurally and functionally undisclosed proteins.
20^225 = about 5x10^292 structurally and functionally undisclosed proteins.
20^275 = an infinite genus of structurally and functionally undisclosed proteins.
It is axiomatic that 20^325, 20^375, 20^425, 20^470 each are also an infinite genus of structurally and functionally undisclosed proteins.
Thus, instant claims reasonably encompass:
an essentially infinite and/or enormously vast genus of about 5x10^292, 4x10^227, 4x10^162, 1x10^130, 3x10^97, 1x10^65, and/or 3x10^32 structurally and functionally undisclosed amino acid sequences that are to have the functional properties of binding an enormously vast genus of about 1x10^52, and/or 3x10^45 structurally and functionally undisclosed “first antigen” amino acid sequences; and
an essentially infinite and/or enormously vast genus of about 5x10^292, 4x10^227, 4x10^162, 1x10^130, 3x10^97, 1x10^65, and/or 3x10^32 structurally and functionally undisclosed amino acid sequences that are to have the functional properties of binding an enormously vast genus of about 1x10^52, and/or 3x10^45 structurally and functionally undisclosed “second antigen” amino acid sequences.
With respect to the therapeutic protein, recited at a high level of generality,
As discussed above, the average eukaryotic protein is about 470 amino acids in length.
20^25 = about 3x10^32 structurally and functionally undisclosed proteins.
20^50 = about 1x10^65 structurally and functionally undisclosed proteins.
20^75 = about 3x10^97 structurally and functionally undisclosed proteins.
20^100 = about 1x10^130 structurally and functionally undisclosed proteins.
20^125 = about 4x10^162 structurally and functionally undisclosed proteins.
20^175 = about 4x10^227 structurally and functionally undisclosed proteins.
20^225 = about 5x10^292 structurally and functionally undisclosed proteins.
20^275 = an infinite genus of structurally and functionally undisclosed proteins.
It is axiomatic that 20^325, 20^375, 20^425, 20^470 each are also an infinite genus of structurally and functionally undisclosed proteins.
While Claims 6-9 recite wherein the therapeutic protein is a chimeric antigen receptor, here too, such is/are recited at a high level of generality, suffering from the same issues discussed above, and fail to make up for the deficiencies of the independent claim.
Rudikoff et al (Single Amino Acid Substitution Altering Antigen-binding Specificity, PNAS 79:1979-1983, 1982) taught that a single amino acid substitution is sufficient to alter the antigen-binding specificity, and thus alters antigen-binding affinity constants.
Srivastava and Riddell (Engineering CAR-T cells: Design concepts, Trends Immunol. 36(8): 494-502; available online July 15, 2015) taught that while the biochemical principles of (Kon)/ (Koff) rates, and binding affinity were recognized in the art for being important parameters when designing CARs (Table 2), such values must be determined empirically to optimally activate T cells for tumor recognition (pgs 500-501, joining para).
Vuet al (U.S. 2015/0368351) disclosed that the same antigen binding domain will have different binding affinity values, corresponding (Koff) values, and corresponding (Kon) values, depending upon the target antigen (Table 6). Thus, knowing the structure of an antigen binding domain does not immediately lead to knowing the corresponding values of binding affinity and kinetics to the corresponding target antigen. Rather, each of the values must be determined empirically.
Given the highly diverse structural nature of antigen binding domains one of ordinary skill in the art generally cannot envision the structure of an antibody by knowing its binding characteristics.
Sela-Culang et al (The structural basis of antibody-antigen recognition, Frontiers in Immunology 4: Article 302, 13 pages, doi: 10.3389/fimmu.2013.00302; available online October 8, 2013) is considered relevant prior art for having taught that while the six CDRs are widely assumed to be responsible for antigen recognition, recent studies and analyses of a growing number of available antibody structures indicate that this assumption is an oversimplification. Some amino acid positions in the CDRs have been shown to never participate in antigen binding, and some amino acid positions in the framework regions, outside the CDRs, often contribute critically to the interaction with antigen (e.g. Abstract).
Rather, some studies indicate that only 20-30% of the CDR residues participate in antigen binding, while the remaining residues are important for maintaining structural conformations of the hypervariable loops (e.g. pg 4, col. 1).
Sela-Culang et al taught that the prior art recognized that simply grafting only the CDRs of a mouse antibody onto a human variable region framework usually results in a significant drop, or a complete loss, of antigen binding. In order to restore antigen binding, one needs to mutate back some of the framework residues to the original mouse antibody (e.g. pg 7, col. 1).
Some of these framework residues that contact and bind the antigen are close in sequence to the CDRs, while other framework residues are far from the CDRs in the primary sequence, but closer proximity in the 3-D structure (e.g. pg 7, col’s 1-2, joining para).
A second category of framework residues that affect antigen binding are those that affect antigen binding indirectly, e.g.:
i) by providing a structural support to the CDRs, enabling them to adopt the right conformation and orientation, shaping the binding site required for antigen binding; or
ii) maintaining the overall structure of the Fv domains by directing the relative orientation of the VH vs VL domains, and thus the orientation of the CDRs relative to each other (e.g. pg 7, col. 2).
Goel et al (Plasticity within the Antigen-Combining Site May Manifest as Molecular Mimicry in the Humoral Immune Response, J. Immunol. 173: 7358-7367, 2004) taught the generation of monoclonal antibodies directed to the same antigen, whereby three antibodies that bind to the same 12-mer epitope/antigen have substantial amino acid diversity in the CDRs (Figure 3) and binding kinetics (Table III, Figure 6).
Poosarla et al (Computational De Novo Design of Antibodies Binding to a Peptide With High Affinity, Biotech. & Bioengin. 114(6): 1331-1342, 2017) designed scFv fragments that bind to the same 12-mer epitope/antigen, and demonstrate substantial diversity in said antibody amino acid sequences (Figure 3). It appears that even though all antibodies bind to the same 12-mer they bind to different epitopes within it.
Edwards et al (The Remarkable Flexibility of the Human Antibody Repertoire; Isolation of Over One Thousand Different Antibodies to a Single Protein, BLyS, J. Mol. Biol. 334: 103-118, 2003) taught the ability to identify over 1000 antibodies composed of structurally different amino acid sequences that bind to a single antigen (see entire paper).
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
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 functional properties of the enormously vast genus of first antigen binding domains, second antigen binding domains, first transcription factors, and second transcription factors, respectively.
Prediction of nucleic acid and 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 enormously vast genera of structurally and functionally undisclosed first antigens, second antigens, first antigen-binding domains, second antigen binding domains, first transcription factors, second transcription factors, second promoters, and third promoters, concordantly and respectively, 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.
With respect to the first and second antigens expressed on the target cell, (ii) and (vi), recited at a high level of generality,
Barrow et al (Tumor Antigen Expression in Melanoma Varies According to Antigen and Stage, Clin. Cancer Res. 12(3): 764-771, 2006) is considered relevant prior art for having taught that tumor antigen expression varies according to the antigen itself, and the stage of cancer disease, whereby the antigen expression may be lost, reduced, increased, fluctuates, or absent (e.g. Table 3).
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
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’).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial first antigen and initial second antigen are to comprise an amino acid sequence, being recognized by and bound to an antigen binding domain on the first and second BTTS, respectively, whereupon the first and second transcription factors are to then bind a second and third promoter, respectively, does not tell you anything at all about:
a) the enormously vast genus of about 1x10^52, and/or 3x10^45 structurally and functionally undisclosed first antigens that are to be recognized and bound to the essentially infinite and/or enormously vast genus of about 5x10^292, 4x10^227, 4x10^162, 1x10^130, 3x10^97, 1x10^65, and/or 3x10^32 structurally and functionally undisclosed first antigen binding domains, nor the corresponding binding affinities, respectively;
b) the enormously vast genus of about 1x10^52, and/or 3x10^45 structurally and functionally undisclosed first antigens that are to be recognized and bound to the essentially infinite and/or enormously vast genus of about 5x10^292, 4x10^227, 4x10^162, 1x10^130, 3x10^97, 1x10^65, and/or 3x10^32 structurally and functionally undisclosed first antigen binding domains, nor the corresponding binding affinities, respectively;
c) the essentially infinite and/or enormously vast genus of about 5x10^292, 4x10^227, and/or 4x10^162 structurally and functionally undisclosed amino acid sequences that are to have the functional properties of being a transcriptional activator upon binding to an essentially infinite and/or enormously vast genus of about 1x10^301, 1x10^150, and/or 1x10^60 structurally and functionally undisclosed “second” promoter nucleic acid sequences; and
d) an essentially infinite and/or enormously vast genus of about 5x10^292, 4x10^227, and/or 4x10^162 structurally and functionally undisclosed amino acid sequences that are to have the functional properties of being a transcriptional activator upon binding to an essentially infinite and/or enormously vast genus of about 1x10^301, 1x10^150, and/or 1x10^60 structurally and functionally undisclosed “third” promoter nucleic acid sequences,
whereby the transcriptional activity of the first transcription factor is to be greater than the transcriptional activity of the second transcription factor;
e) an essentially infinite and/or enormously vast genus of about 1x10^301, 1x10^150, and/or 1x10^60 structurally and functionally undisclosed first and second transcription factor binding site nucleic acid sequences; and
f) the essentially infinite and/or enormously vast genus of about 5x10^292, 4x10^227, and/or 4x10^162 structurally and functionally undisclosed amino acid sequences that are to have the functional properties of being a therapeutic protein.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed class gene circuit expression cassette components each encompass an infinite and/or enormously vast genus of structurally and functionally undisclosed nucleic acid and amino acid molecules, respectively.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
At best, Applicant’s working examples are directed to a GAL4-VP64 “stronger” transcription factor and a LexA-VP64 “weaker” transcription factor (e.g. [0017]).
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).
3. Claim(s) 25-26 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.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
Claim 25 recites a method of treating a subject for a disease, the method comprising the step of administering to said subject a host cell of Claim 1.
The breadth of the claims requires the administration of just one cell.
The claims are enormously broad for encompassing essentially all forms of extant living prokaryotic and eukaryotic host cells. [00182] discloses the host cell may be a bacterial cell, or a generic eukaryotic cell, including fungal yeast [00185], and thus encompass about 0.8 to 1.6 million species of prokaryotes (Louca et al, A census-based estimate of Earth’s bacterial and archeal diversity, PLoS Biology 17(2): e3000106, 30 pages, 2019) and about 8.7 million species of eukaryotic organisms, including about 250,000 species of eukaryotic protists, about 100,000 species of fungi, about 250,000 species of plants, and about 1,000,000 species of animals, including worms, insects, sponges, jellyfish, fish, lizards, and mammals (Sweetlove, Nature News doi:10.1038/news.2011.498; August, 2011; Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021).
The art does not teach, and the specification fails to disclose, that administration of just one bacterium, e.g. Pseudomonas aeruginosa, comprising the claimed class of first, second, and third gene circuit expression cassette components, each encompassing an infinite and/or enormously vast genus of structurally and functionally undisclosed nucleic acid and amino acid molecules, respectively, will necessarily and predictably achieve a real-world, clinically meaningful therapeutic result of treating cancer, an autoimmune disease, fibrosis, a neurodegenerative disease, diabetes, or an infectious disease, for example.
The art does not teach, and the specification fails to disclose, that administration of just one protozoan, e.g. Giardia lamblia, comprising the claimed class of first, second, and third gene circuit expression cassette components, each encompassing an infinite and/or enormously vast genus of structurally and functionally undisclosed nucleic acid and amino acid molecules, respectively, will necessarily and predictably achieve a real-world, clinically meaningful therapeutic result of treating cancer, an autoimmune disease, fibrosis, a neurodegenerative disease, diabetes, or an infectious disease, for example.
The art does not teach, and the specification fails to disclose, that administration of just one fungal cell, e.g. Candida albicans, comprising the claimed class of first, second, and third gene circuit expression cassette components, each encompassing an infinite and/or enormously vast genus of structurally and functionally undisclosed nucleic acid and amino acid molecules, respectively, will necessarily and predictably achieve a real-world, clinically meaningful therapeutic result of treating cancer, an autoimmune disease, fibrosis, a neurodegenerative disease, diabetes, or an infectious disease, for example.
The art does not teach, and the specification fails to disclose, that administration of just one plant cell, e.g. Arabidopsis thaliana, comprising the claimed class of first, second, and third gene circuit expression cassette components, each encompassing an infinite and/or enormously vast genus of structurally and functionally undisclosed nucleic acid and amino acid molecules, respectively, will necessarily and predictably achieve a real-world, clinically meaningful therapeutic result of treating cancer, an autoimmune disease, fibrosis, a neurodegenerative disease, diabetes, or an infectious disease, for example.
The art does not teach, and the specification fails to disclose, that administration of just one animal cell, e.g. nematode worm cell, such as Nippostrongylus brasiliensis, comprising the claimed class of first, second, and third gene circuit expression cassette components, each encompassing an infinite and/or enormously vast genus of structurally and functionally undisclosed nucleic acid and amino acid molecules, respectively, will necessarily and predictably achieve a real-world, clinically meaningful therapeutic result of treating cancer, an autoimmune disease, fibrosis, a neurodegenerative disease, diabetes, or an infectious disease, for example.
The art does not teach, and the specification fails to disclose, that administration of just one animal cell, e.g. insect cell, such as Drosophila melanogaster, comprising the claimed class of first, second, and third gene circuit expression cassette components, each encompassing an infinite and/or enormously vast genus of structurally and functionally undisclosed nucleic acid and amino acid molecules, respectively, will necessarily and predictably achieve a real-world, clinically meaningful therapeutic result of treating cancer, an autoimmune disease, fibrosis, a neurodegenerative disease, diabetes, or an infectious disease, for example.
At best, Applicant’s working examples are directed to CAR T cells (e.g. [00216]).
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed method encompasses administration to the subject just one cell of enormously vast genus of about 1.6 million prokaryotic host cell species and about 8.7 million eukaryotic host cell species expressing the claimed genetic circuit.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
At best, Applicant’s working examples are directed to CAR T cells (e.g. [00216]).
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).
4. Claims 25-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a disease in a subject, the method comprising the step of administering a pharmaceutical composition comprising a population of T cells comprising the genetic circuit of Claim 1, wherein the therapeutic protein is a chimeric antigen receptor, does not reasonably provide enablement for administration to the subject just one cell of enormously vast genus of about 1.6 million prokaryotic host cell species and about 8.7 million eukaryotic host cell species expressing the claimed genetic circuit will necessarily and predictably achieve a real-world, clinically meaningful therapeutic result of treating cancer, an autoimmune disease, fibrosis, a neurodegenerative disease, diabetes, or an infectious disease.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection(s).
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed method encompasses administration to the subject just one cell of enormously vast genus of about 1.6 million prokaryotic host cell species and about 8.7 million eukaryotic host cell species expressing the claimed genetic circuit.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
At best, Applicant’s working examples are directed to CAR T cells (e.g. [00216]).
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 § 103
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 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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
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.
5. Claims 1, 3-9, and 20-21 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Daringer et al (Modular Extracellular Sensor Architecture for Engineering Mammalian Cell-based Devices, ACS Synth. Biol. 3: 892-902, 2014) in view of McAdams et al (Circuit Simulation of Genetic Networks, Science 269 (5224): 650-656, 1995), Xie et al (Multi-Input RNAi-Based Logic Circuit for Identification of Specific Cancer Cells, Science 333(6047): 1307-1311, 2011), and Lim et al (WO 17/193059; Applicant’s own work not cited in an IDS).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 1, Daringer et al is considered relevant prior art for having taught a gene circuit comprising:
a) a first expression cassette comprising a promoter operably linked to a first binding-triggered transcriptional switch (BTTS) comprising a first extracellular binding domain, a transmembrane domain, and a first transcription factor,
whereupon binding of the first BTTS to a first target ligand releases the first transcription factor into the cytoplasm of the host cell;
b) a second expression cassette comprising a promoter operably linked to a second binding-triggered transcriptional switch (BTTS) comprising a second extracellular binding domain, a transmembrane domain, and a second transcription factor,
whereupon binding of the second BTTS to a second target ligand releases the second transcription factor into the cytoplasm of the host cell; and
c) a third expression cassette comprising a promoter operably linked to the artisan’s coding sequence of interest,
whereby transcription of the third expression cassette is induced by the first and second transcription factors (e.g. Abstract figure), as shown below:
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Daringer et al taught that the Modular Extracellular Sensor Architecture (MESA) system provides a framework readily adaptable for novel input ligands, output transcription factors or other artisan’s protein of interest, and applications of interest, including chimeric antigen receptor technologies to increase the safety and efficacy of cell-based immunotherapies (e.g. pg 900, col. 1).
Daringer et al taught that it should be possible to multiplex MESA receptors, coupling multiplex receptors to logic-based gene circuits (e.g. pg 900, col. 1).
Daringer et al do not teach the expression of the second expression cassette is induced by the first transcription factor.
However, prior to the effective filing date of the instantly claimed invention, McAdams et al is considered relevant prior art for having taught a gene circuit comprising:
a) a first expression cassette comprising a promoter operably linked to a first transcription factor (A);
b) a second expression cassette comprising a promoter operably linked to a second transcription factor (C),
whereupon binding of the first transcription factor to the promoter of the second expression cassette induces expression of the second transcription factor; and
c) a third expression cassette comprising the artisan’s coding sequence of interest (B),
whereby expression of the third expression cassette is induced by the second transcription factor (e.g. pg 650, col. 3, Figure 1a), as shown below:
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Similarly, Xie et al is considered relevant prior art for having taught a gene circuit comprising:
a) a first expression cassette comprising a promoter operably linked to a first transcription factor (rtTA);
b) a second expression cassette comprising a promoter operably linked to a second transcription factor (LacI),
whereupon binding of the first transcription factor to the promoter of the second expression cassette induces expression of the second transcription factor; and
c) a third expression cassette comprising a promoter operably linked to the artisan’s coding sequence of interest,
whereby expression of the third expression cassette is induced by the second transcription factor (e.g. Figure 1b), as shown below:
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292
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Neither Daringer et al, McAdams et al, nor Xie et al teach wherein the third expression cassette comprises a sequence encoding a therapeutic protein.
However, prior to the effective filing date of the instantly claimed invention, Lim et al (Applicant’s own work) is considered relevant prior art for having disclosed a gene circuit comprising:
a) a first expression cassette comprising a promoter operably linked to a first binding-triggered transcriptional switch (BTTS) comprising a first extracellular binding domain, a transmembrane domain, and a first transcription factor (syn. a first SynNotch receptor, [0061]),
whereupon binding of the first BTTS to a first target ligand releases the first transcription factor into the cytoplasm of the host cell;
b) a second expression cassette comprising a promoter operably linked to a second binding-triggered transcriptional switch (BTTS) comprising a second extracellular binding domain, a transmembrane domain, and a second transcription factor, (syn. a second SynNotch receptor, [0061]),
whereupon binding of the first BTTS to a first target ligand releases the first transcription factor into the cytoplasm of the host cell (e.g. [0044]), and
whereby the second expression cassette is induced by the first antigen-triggered polypeptide binds to the first target antigen of the target antigen pair (e.g. [0047-48]); and
c) at least a third expression cassette comprising a promoter operably linked to the artisan’s coding sequence of interest, e.g. chimeric antigen receptor,
whereby transcription of the third expression cassette is induced by the first or second transcription factor (e.g. Figure 3B), as shown below:
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Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, genetics, and the design of gene circuits, including synthetic gene circuits. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. 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). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first gene circuit comprising two parallel sensory AND input gene circuits and an output circuit (syn. gate) that expresses the artisan’s gene of interest in response to the sensory input gene circuits, as taught by Daringer et al and Lim et al, with a second gene circuit comprising two serial AND sensory input gene circuits and an output circuit (syn. gate) that expresses the artisan’s gene of interest in response to the sensory input gene circuits, as taught by McAdams et al and Xie et al, with 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.
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to modify a parallel AND gene circuit of Daringer et al and Lim et al to a serial AND gene circuit expressing a therapeutic polypeptide with a reasonable expectation of success because it is obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” One of ordinary skill in the art would have understood how to design synthetic gene circuits with which to identify the finite potential options, parallel or serial, AND sensory input circuits could have pursued the known potential options with a reasonable expectation of success, as demonstrated by McAdams et al and Xie et al. An artisan would be motivated to modify or substitute a first gene circuit comprising two parallel sensory input gene circuits and an output circuit (syn. gate) that expresses the artisan’s gene of interest in response to the sensory input gene circuits to/with a second gene circuit comprising two serial sensory input gene circuits and an output circuit (syn. gate) that expresses the artisan’s gene of interest in response to the sensory input gene circuits because those of ordinary skill in the art previously recognized the scientific and technical concepts that gene logic circuits can be designed in either parallel or series arrangement (syn. known options), as successfully demonstrated by McAdams et al and Xie et al, whereby Applicant previously disclosed that expression of a functional therapeutic protein (output circuit) is only produced when both the first BTTS and second BTTS (first and second sensory input AND circuits) recognize their target antigens, respectively (e.g. [0047]; Figure 3B).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 3, Daringer et al taught wherein the transcription factor is a tet transactivator (tTA) (e.g. 895, col. 1).
Lim et al disclosed wherein the transcription factor is a tet transactivator (tTA) (e.g. [00111], “tetracycline regulated promoters (e.g. (TetActivators, TetON, TetOFF)”).
With respect to Claim 4, Daringer et al taught wherein the transcription factor is released from the BTTS via proteolytic cleavage upon antigen binding to the antigen (entire paper).
Lim et al disclosed wherein the transcription factor is released from the BTTS via proteolytic cleavage upon antigen binding to the antigen (e.g. [0061]).
With respect to Claim 5, Daringer et al taught wherein the binding-triggered transcriptional switch is a Modular Extracellular Sensor Architecture (MESA) (entire paper).
Lim et al disclosed wherein the first and second BTTS are SynNotch receptors (e.g. Figure 3B).
With respect to Claims 6-9, Lim et al disclosed wherein the therapeutic protein is a chimeric antigen receptor (e.g. Figure 3B).
With respect to Claim 20, Lim et al disclosed wherein the first and second BTTS are SynNotch receptors (e.g. Figure 3B).
With respect to Claim 21, Daringer et al taught wherein the host cell is an immune cell (e.g. pg 900, col. 1, CAR technologies, cell-based immunotherapy).
Lim et al disclosed wherein the host cell is an immune cell (e.g. [0095-96]; Figure 3b).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
6. Claim(s) 3-9 and 20-21 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Daringer et al (Modular Extracellular Sensor Architecture for Engineering Mammalian Cell-based Devices, ACS Synth. Biol. 3: 892-902, 2014) in view of McAdams et al (Circuit Simulation of Genetic Networks, Science 269 (5224): 650-656, 1995), Xie et al (Multi-Input RNAi-Based Logic Circuit for Identification of Specific Cancer Cells, Science 333(6047): 1307-1311, 2011), Lim et al (WO 17/193059; Applicant’s own work not cited in an IDS), as applied to Claims 1, 3-9, and 20-21 above, and in further view of Arkin et al (A Standard Parts List for Biological Circuitry, DARPA White Paper, Massachusetts Institute of Technology, Department of Biological Engineering, 7 pages, hdl.handle.net/1721.1/29794, 1999), Roybal et al (Precision Tumor Recognition by T Cells With Combinatorial Antigen-Sensing Circuits, Cell 164: 770-779, 2016; Applicant’s own work not cited in an IDS), and Ting et al (Focusing Transgene Expression in Drosophila by Coupling Gal4 With a Novel Split-LexA Expression System, Genetics 188: 229-233, 2011).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Neither Daringer et al, McAdams et al, Xie et al, nor Lim et al teach/disclose wherein the first and second transcription factors are Gal4 or LexA.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 3, Arkin et al taught that the standard parts of biological circuit design include exogenous transcription factors such as Gal4 and LexA (e.g. pg 2, Promoter Control Engineering).
Roybal et al is considered relevant prior art for having taught a host cell comprising a SynNotch gene circuit, wherein the first transcription factor is GAL4 (e.g. Figure 3A).
Ting et al is considered relevant prior art for having taught a host cell comprising a gene circuit, wherein the first transcription factor is Gal4 and the second transcription factor is LexA (e.g. Figure 2C).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. 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). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first and second transcription factors with Gal4 and LexA transcription factors in a gene circuit, including a SynNotch gene circuit, with 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.
The motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. MPEP §2144.
An artisan would be motivated to substitute a first and second transcription factors with GAL4 and LexA transcription factors in a gene circuit, including a SynNotch gene circuit, because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) Gal4 and LexA transcription factors were standard parts of biological circuits (Arkin et al);
ii) Applicant themselves previously successfully demonstrated the use of Gal4 transcription factor in a SynNotch gene circuit (Roybal et al); and
iii) gene circuits combining Gal4 and LexA transcription factors were previously successfully demonstrated (Ting et al).
One of ordinary skill in the art could have combined the Gal4 and LexA transcription factors in a SynNotch gene circuit as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 4, Daringer et al taught wherein the transcription factor is released from the BTTS via proteolytic cleavage upon antigen binding to the antigen (entire paper).
Lim et al disclosed wherein the transcription factor is released from the BTTS via proteolytic cleavage upon antigen binding to the antigen (e.g. [0061]).
Ting et al taught wherein the transcription factor is released from the BTTS via proteolytic cleavage upon antigen binding to the antigen (e.g. Figure 1, legend).
With respect to Claim 5, Daringer et al taught wherein the binding-triggered transcriptional switch is a Modular Extracellular Sensor Architecture (MESA) (entire paper).
Lim et al disclosed wherein the first and second BTTS are SynNotch receptors (e.g. Figure 3B).
Ting et al taught wherein the BTTS is a SynNotch receptor (e.g. Figure 3A).
With respect to Claims 6-9, Lim et al disclosed wherein the therapeutic protein is a chimeric antigen receptor (e.g. Figure 3B).
Ting et al taught wherein the therapeutic protein is a chimeric antigen receptor (e.g. Figure 3A).
With respect to Claim 20, Lim et al disclosed wherein the first and second BTTS are SynNotch receptors (e.g. Figure 3B).
Ting et al taught wherein the BTTS is a SynNotch receptor (e.g. Figure 3A).
With respect to Claim 21, Daringer et al taught wherein the host cell is an immune cell (e.g. pg 900, col. 1, CAR technologies, cell-based immunotherapy).
Lim et al disclosed wherein the host cell is an immune cell (e.g. [0095-96]; Figure 3b).
Ting et al taught wherein the host cell is an immune cell (e.g. Figure 3).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
7. Claims 25-26 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Daringer et al (Modular Extracellular Sensor Architecture for Engineering Mammalian Cell-based Devices, ACS Synth. Biol. 3: 892-902, 2014) in view of McAdams et al (Circuit Simulation of Genetic Networks, Science 269 (5224): 650-656, 1995), Xie et al (Multi-Input RNAi-Based Logic Circuit for Identification of Specific Cancer Cells, Science 333(6047): 1307-1311, 2011), Lim et al (WO 17/193059; Applicant’s own work not cited in an IDS), as applied to Claims 1, 3-9, and 20-21 above.
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
The teachings/disclosures of Daringer et al, McAdams et al, Xie et al, and Lim et al are discussed above, rendering the cell of Claim 1 obvious.
With respect to Claim 25, Lim et al disclosed a method of treating a subject for a disease, the method comprising the step of administering to said subject a cell comprising the three-component genetic circuit (e.g. claim 17, [00405]).
With respect to Claim 26, Lim et al disclosed wherein the disease is cancer (e.g. claim 18, [00406]).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. 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). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to a CAR T cell comprising a gene circuit comprising two serial AND sensory input BTTS gene circuits and an output circuit (syn. gate) that expresses the artisan’s chimeric antigen receptor of interest in response to the sensory input gene circuits in a method of treating a disease in a subject, e.g. cancer, with a reasonable expectation of success because Applicant themselves (Lim et al) previously disclosed CAR T cells comprising a gene circuit comprising two AND sensory input BTTS gene circuits and an output circuit (syn. gate) that expresses the artisan’s chimeric antigen receptor of interest in response to the sensory input gene circuits in a method of treating a disease in a subject, e.g. cancer.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Conclusion
8. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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