DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2 Applicant's amendment, filed on 06/13/2024, is acknowledged.
3. Claims 1-21 are pending.
4. Applicant’s election with traverse of Group I, claims 1-6 directed to an engineered a T-cell receptor (TCR) specific for human MAGE-A3 and the species of D28H and SEQ ID NOs: 3, 5 and 13, filed on 07/10/2026, is acknowledged.
5. Claims 7-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
6. Claims 1-6 are under examination as they read on an engineered a T-cell receptor (TCR) specific for human MAGE-A3 and the species of D28H and SEQ ID NOs: 3 (clone 20a-18), 5 (clone 20a-new 12) and 13.
7. Applicant’s IDS, filed 08/28/2023, 03/19/2025 and 07/10/2026 is acknowledged.
8. claim 4 is objected because it appears that the 3rd species “D28” should be “D28G”. The claims list species using commas “,” and semicolons “;”. Moreover, there is no conjunction “and / or” separating the “;” and/or “,” amino acid modifications.
9. The specification at page 43, [0177] is objected to because it refers to Figure S3C) and Figure S3D-S3E. Such figures do not exist in the instant specification. It appears that the specification refers to Supplementary Materials for Xiang Zhao et al. Tuning T cell receptor sensitivity through catch bond engineering. Science 376, eabl5282 (2022), DOI: 10.1126/science.abl5282. Correction is required.
10. It is noted that clones 27a-5 (SEQ ID NO: 6) and 68a-2 (SEQ ID NO: 7) are identical comprising the same mutations D28G, A30H, Q54R, S54E.
11. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
12. Claim 5-6 are rejected under 35 U.S.C. 112(d) or 35 U.S.C. 112 (pre-AIA ), 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
(i) Claim 5 which depends from claim 1 recites “or a variant derived therefrom” however claim 1 is limited to at least one modification selected from D28, A30, I51, Q52, S53 and S54 of a mature version of SEQ ID NO: 1 or SEQ ID NO: 1 , however claim 5 encompass a genus of variants that are not limited to D28, A30, I51, Q52, S53 and/or S54.
(ii) Similarly, claim 6 recites “at least 95% sequence identity to . . SEQ ID NO: 2-SEQ ID NO: 15”, however claim 1 is limited to at least one modification selected from D28, A30, I51, Q52, S53 and S54 of a mature version of SEQ ID NO: 1 or SEQ ID NO: 1, however claim 6 encompass a genus of up to 5% variants that are not limited to D28, A30, I51, Q52, S53 and/or S54. For example, SEQ ID NO: 1 is 274 amino acids long with a change in D28 which results in 99.6% identical to SEQ ID NO: 1.
Claims 5-6 do not further limit the scope of claim 1 but rather broaden the scope of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
13. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
14. Claim 4 is rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
(a) The recitation “S54D, S54H” is indefinite because the claim is missing the conjunction “and” or “or” in listing the amino acid modification species.
15. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(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.
16. Claims 1-6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 encompasses a broad genus of human MAGE-A3 comprising a genus of at least one amino acid modification in the alpha (α) chain of SEQ ID NO: 1 at D28, A30, I51, Q52, S53 and/or S54 to enhance target activation potency and lacking the TCRβ chain. That is claim 1 encompasses up to 6 amino acids modification and since there are 20 naturally occurring amino acids, then the claim encompasses up to 206 = 64,000,000 different mutations in the TCRα chain and lacking the TCRβ.
Claim 4 encompasses a combination of up to 38,760 modifications in TCRα chain of SEQ ID NO: 1 and lacks the TCRβ chain.
Claim 5 encompasses unknown variants of the already modified TCRα chains of SEQ ID NOs: 2-15 and lacking the TCRβ chain.
Claim 6 encompasses up to 5% modification in the already modified TCRα chains of SEQ ID NO: 2-15 and lacking the TCRβ chain. That is 5% of 274 amino acids of SEQ ID NOs: 2-15 is ~14 amino acids to be modified. That is 2014 which is 163,840,000,000,000 (163.84 trillion modification) in each SEQ ID NO.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of enhance target activation potency wherein the 3D log KD(μM) for MAGE-A3 and HLA-A is from about 0.5 to about 100 μM. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.
The specification at [0174] discloses an alternative TCR engineering strategy that we call “catch bond fishing” that harnesses a biophysical parameter mediating many adhesive cell surface protein-protein interactions. As a proof of principle experiment, we converted a non-stimulatory TCR into a potently activated TCR by screening of catch bond fishing TCR display libraries that produced TCR with comparable 3D binding affinities to the non-responsive parent TCR clone, but high sensitivity to functional signaling that was in all cases paralleled by the acquisition of catch bonds. We then applied the catch bond engineering strategy to a melanoma antigen MAGE-A3-specific TCR with extremely weak activation and killing capacity. We identified several TCR mutants with target killing potency equal or superior to that of the clinical affinity-matured version of the A3A TCR that showed off target cross-reactivity and toxicity. In spite of this gain in response sensitivity, our catch bond engineered TCRs maintained physiological affinities and did not cross-react with either the known off-target antigen as compared to the affinity-matured clinical TCR or with a wide array of HLA-associated peptides from the human proteome. Together, these findings provide additional strong evidence for the important role of catch bonds in efficacious TCR-ligand interactions and suggest that catch bond recruitment can be exploited as a general approach to overcome a major limitation of TCR-T therapy.
[0175] Design of ‘catch bond fishing’ libraries. Our previous studies showed that although TCR55 binds to an HIV peptide (Pol448-456) presented by the HLA-B35 MHC molecule with physiological affinities, this TCR-pMHC interaction does not produce measurable T cell activation, or form catch bonds during the binding event. However, HIV peptide mutants isolated from HLA-B35 yeast pMHC libraries, such as pep20, gained the capacity to form catch bonds with TCR55 and potently activated T cells bearing this receptor, while maintaining comparable affinity to the non-stimulatory parent pMHC. Here we asked if, in a reciprocal manner, a functional screen could isolate mutants of TCR55 that enable functional T cell responses evoked by the ‘non-stimulatory’ HIV peptide in conjunction with acquisition of catch bond capacity.
[0179] Single amino acid substitutions in TCR55 trigger activation through catch bond formation. We carried out three rounds of FACS-sorting selections on the TCR55α CDR library (diversity: 1,728) and enriched a population with a tetramer-low, CD69-high staining phenotype. Approximately 100 single cell clones were recovered and individually tested for activation by the HIV(Pol) peptide. The two clones (clone 8 and clone 17) that showed the most potent response to this pMHC ligand (Figure S3C), encoded identical TCR mutations on TCR55α chain—S28G and A98H. To directly examine if the identified mutations conferred increased potency, SKW3 T cells were transduced with the TCR55α-S28G A98H and WT TCR55β chain and stimulated by B35-associated HIV peptide. To deconvolute which mutation was responsible for the activation, we tested the mutations individually (Figure S3D-S3E) and found that the single mutation of alanine to histidine in the TCR55α CDR3 was sufficient to endow the non-responsive TCR55 with the ability to be signal for activation upon exposure to the B35-HIV pMHC.
[0182] We carried out a parallel screen on a TCR55β CDR library (diversity: 20,736) using the same workflow, and identified a TCR55 variant, clone 36, that exhibited a high level of T cell activation by B35-HIV(Pol). Clone 36 contained two mutations: aCDR1 mutation TCR55β-N28Q, and a CDR2 mutation TCR55β-A50D. We identified the isolated TCR55β-A50D mutation as necessary and sufficient to enable T cell activation by B35-HIV. Replacing the TCR553-A50 position with alternative amino acids showed that aspartate, glutamate, phenylalanine, histidine, asparagine, glutamine, serine, threonine, and tyrosine supported TCR55 mutant responses to B35-HIV to different degree, while cysteine, lysine, arginine, and tryptophan did not support effective signaling.
The specification at [0187] discloses approximately 100 single cell clones were selected from the enriched population and tested for TCR-dependent activation. We isolated 13 distinct mutant-transduced SKW3 clones that showed enhanced responsiveness to the MAGE-A3 peptide at a concentration unable to trigger T cells expressing the parental WT TCR. By comparing the Emax of the TCR mutants. 8 clones as “high-potency” mutants compared to the A3A TCR, and 5 clones as “intermediate-potency” mutants. We measured SPR 3D KD for six high-potency mutants and two intermediate-potency mutants binding to HLA-A1-MAGE-A3. The affinities ranged from KD=10 to 50 μM, significantly lower affinities than that of A3A which is KD=1.24 μM. We did not observe a correlation between Emax vs 3D affinity (R2=0.3718) but observed a weak correlation between EC50 and affinity (R2=0.5998). We tested if the 8 high-potency mutants showed cross-reactive functional responses to the TITIN peptide. The A3A-transduced SKW3 cells were strongly activated by the TITIN pMHC ligand. Four mutants (20a-18 (SEQ ID NO:3, 20a-new 12 (SEQ ID NO:5), 94a-14 (SEQ ID NO:9), and 94a-30 (SEQ ID NO: 10)) exhibited no cross-reactivity with the TITIN peptide, whereas the remaining four displayed very weak activation by TITIN only at high peptide concentrations.
[0190] To examine if TCR clones 94a-14 and 20a-18 exhibited cross reactivity to TITIN, primary human T cells transduced with the respective TCRs were co-cultured with MAGE-A3 or TITIN peptide-pulsed antigen-presenting cells. While 20a-18 (SEQ ID NO: 3) or 94a-14 (SEQ ID NO: 9) showed enhanced cytotoxicity, degranulation, and cytokine secretion after coculturing with MAGE-A3 pulsed cells, none of these TCR clones responded to the presented TITIN peptide. Similarly, the 20a-5 (SEQ ID NO: 4) and 27a-5 (SEQ ID NO: 6) clones mediated potent cytotoxic responses to MAGE-A3 but only minimal cross-reactivity to TITIN at high concentrations of peptide.
[0167] Shown in FIG. 14 are sequences of all MAGE TCR mutants, SEQ ID NO:1-16. All the mutants only have mutations in TCR alpha chain residues of Asp28, Ala30, Ile51, Gln52, Ser53 and Ser54. The specific mutated residues of each mutate are listed here.
αMAGE Clone SEQ ID NO Mutations
TCRα 1 wildtype
A3A 2 51VRPY54 (i.e., I51V, Q52R, S53P, S54Y)
20a-18 3 D28H, A30H
20a-5 4 D28G, A30H, Q52R, S54N
20a-new 12 5 D28H, A30H, Q52R, S54R
27a-5 6 D28G, A30H, Q52R, S54E
29a-7 7 D28G, A30H, Q54R, S54E
68a-2 8 D28N, A30H, Q52R, S54D
94a-14 9 D28G, A30S, Q52R
94a-30 10 D28K, A30E, Q52R
68a-68 11 D28K A30N, Q52R, S54D
68a-new 9 12 D28N, A30H, S54H
--- 13 D28H, A30H, Q52H, S54H
94-10 14 D28S, A30A, Q52R, S54D
20a-5 15 D28N, A30G, Q52R
TCRβ 16 wildtype
The claims encompass a broad genus of human MAGE-A3 comprising a genus of at least one amino acid modification in the alpha (α) chain of SEQ ID NO: 1 at D28, A30, I51, Q52, S53 and/or S54 to enhance target activation potency and lacking the TCRβ chain. That is claim 1 encompasses up to 6 amino acids modification and since there are 20 naturally occurring amino acids, then the claim encompasses up to 206 = 64,000,000 different mutations in the TCRα chain and lacking the TCRβ, a combination of up to 38,760 modifications in TCRα chain of SEQ ID NO: 1 and lacks the TCRβ chain, unknown variants of the already modified TCRα chains of SEQ ID NOs: 2-15 and lacking the TCRβ chain and up to 5% modification in the already modified TCRα chains of SEQ ID NO: 2-15 and lacking the TCRβ chain. That is 5% of 274 amino acids of SEQ ID NOs: 2-15 is ~14 amino acids to be modified. That is 2014 which is 163,840,000,000,000 (163.84 trillion modification) in each SEQ ID NO.
Absent any teaching of structure-function relationships, the skilled in the art cannot determine the critical amino acids in the MAGE-A3 in the recited sequence and also possess the recited function. See AbbVie Deutschland GmbH v. Janssen Biotech, Inc. (Fed. Cir. 2014).
The Specification fails to provide adequate written description support for a genus of modified TCR specific for human MAGE-A3 having the desired functional properties required to practice the claimed enhancing target activation potency.
The facts of Abbvie parallel the claimed invention and provide significant guidance on the inherent unpredictability of protein engineering and the effect of amino acid substitutions on protein function. Abbvie is similar to the Federal Circuit's discussion in Novozymes A/S et al. v. Dupont Nutrition Biosciences APS et al., 2013 WL 3779376, Case No. 2012-1433, C.A.Fed; in both, the Federal Circuit emphasized the unpredictability in the art associated with changes in a parent enzyme or protein that can be effected at one or more positions in the sequence by amino acid addition, deletion, or substitution with at least nineteen other possibilities, e.g. counting natural amino acid residues. The basis of the unpredictability is rooted in the same principles that make improvements rare, namely that numerous subtle differences between amino acid residues determine protein binding and function. Because the subtle energetic contributions of each of these interactions is extraordinarily difficult to precisely quantify, and because the number of these interactions is so high even for a single protein-protein interface, innumerable small inaccuracies are amplified into unpredictability. This unpredictability is axiomatic in the field of protein engineering.
In Novozymes, Defendants-Appellees DuPont Nutrition Biosciences PS et al. ("DuPont") sought to invalidate Novozymes' U.S. Patent No. 7,713,723 (the "723"), arguing insufficient written description for the '723 claims under 35 U.S.C. §112. In particular, DuPont argued a failure of U.S. Provisional Application No. 60/249,104, filed November 16, 2000 (the "2000 application") to support the claimed proteins. In relevant portion, claim I of Novozymes' '723 patent is directed to:
1. An isolated variant of a parent alpha-amylase, wherein:
(a) the variant has at least 90% sequence identity to SEQ ID NO: 6 [BSG alpha-amylase],
(b) the variant comprises a substitution of serine at position 239 relative to the parent alpha-amylase, using the amino acid sequence of SEQ ID NO: 8 [BLA alpha-amylase] for determining position numbering, and
(c) the variant has increased thermostability relative to the parent alpha-amylase, wherein thermostability is determined at pH 4.5, 90°C. and 5 ppm calcium and has alpha-amylase activity.
As outlined by the Federal Circuit, Novozymes identified 33 different possible mutation positions in the approximately 500 amino acids that make up a Bacillus amylase, using both rational protein design as well as empirical random mutagenesis. Novozymes identified 7 potential parent Bacillus enzymes, 33 target positions in each parent enzyme, and the number of potential mutations at each position, such that the Federal Circuit recognized that the specification spanned a potentially wide range of potential variants. The Federal Circuit went on to discuss how little data was actually present in the 2000 specification to support the claim:
For example, one of the seventeen positions identified by rational protein design was position 239, occupied by the amino acid serine (abbreviated as "S") in the disclosed parent alpha-amylase proteins. Many mutations would be possible at position 239, such as an enumerated variant that would require replacing the original serine with the amino acid tryptophan (abbreviated as "W")-a substitution mutation that can be expressed as "S239W." See id. col. 8 1. 12. The 2000 application includes pages of similar exemplary substitutions, presented alone and in double, triple, or larger combinations, but the application does not state that any one of the thirty-three disclosed mutations sites is preferred over any other and does not state whether single or combined mutations are preferred. See id. col. 8 1. 25 - col. 16 1. 37.
Finally, the 2000 application provided two examples with empirical data confirming the enhanced stability of selected variants harboring mutations at the sixteen positions that were identified through random mutagenesis. See id. col. 25 1. 1 - col. 26 1. 65. No such data were disclosed regarding the activity or thermostability of any of the seventeen positions that had been identified through rational protein design, however. Indeed, later experiments revealed that some of the seventeen predicted positions did not yield any thermostable variants, and even for many of those that did, only a minority of substitutions actually had the desired effect. For example, no substitutions at predicted positions 179 or 180 actually led to increased thermostability, and thirteen of the nineteen possible substitutions at position 239 proved similarly ineffective, including the disclosed S239W mutation. Emphasis added; see pages 7 to 8. Of particular import in the Novozymes case is the Federal Circuit's acknowledgement of the inherent unpredictability of protein engineering. As noted in para 3, pg. 5 of Novozymes:
The effects of any given mutation or combination of mutations in a variant can differ depending on the position(s) modified and the specific mutation implemented at each position. Some mutations may have no discernible effect on enzyme function, some may lead to varying degrees of instability or functional impairment, and some may actually improve enzyme activity or impart other desirable properties, such as improved stability at high temperatures.
The Federal Circuit has again recently discussed the inherent unpredictability of protein engineering in the Abbvie case, Abbvie Deutschland Gmbh & Co KG, Abbvie Bioresearch Center, Inc., and Abbvie Biotechnology, Ltd., v. Janssen Biotech In. And Centocor Biologics, LLC, Case No. 2013-1338 and 2013- 1346, C.A.Fed. ("Abbvie"). While Abbvie, similar to the previously discussed Novozymes case, is concerned with the written description requirement under §112, the Federal Circuit reiterates the inherent unpredictability of protein engineering in Abbvie: For example, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 ("[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology."); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation. Instead, AbbVie used a trial and error approach to modify individual amino acids in order to improve the IL-12 binding affinity. Moreover, the '128 and '485 patents do not describe any common structural features of the claimed antibodies. The asserted claims attempt to claim every fully human IL-12 antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity, and cover an antibody as different as Stelara, whereas the patents do not describe representative examples to support the full scope of the claims.
The facts of Abbvie parallel those of the instant case and provide significant guidance on the inherent unpredictability of protein engineering and the effect of amino acid substitutions on protein function. The question is not whether one of skill knows how to generate the an modifications in human MAGE-A3 and screening for the one that works, but whether the specification sufficiently describes the specific substitutions in the MAGE-A3 that correlate with the functions of enhance target activation potency having 3D log KD (µM) for MAGE-A3 and HLA-A1 is from about 0.5 to about 100 µM. Note that even specific substitution in position D28, A30, I51, Q82, S53 and S54 does not appear to yield a variant that enhance target activation potency having 3D log KD (µM) for MAGE-A3 and HLA-A1 is from about 0.5 to about 100 µM and treat melanomasmall cell lung cancer, hematologic malignancies, neoplasms of breast, skin, glioma, neuroblastoma, intestine, colorectal, ovary and the kidney.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative modified αβT cell receptor specific for human MAGE-A falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406. Applicant has provided the 14 sequences comprising SEQ ID NO: 2-15, no other variants are disclosing to have the claimed function of enhancing target activation potency. Recitation of specific amino acid substitutions in the D28, A30, I51, Q52, S53 and S54 are not representative of the genus. Thus, under Lilly and its progeny, their Specification would not have shown possession of a sufficient number of sequences failing within their potentially large genus to establish possession of their claimed genus. Cf. Enzo, 323 F.3d at 964, 63 USPQ2d at 1612 (“if the functional characteristic of … binding to [EphrinB2] were coupled with a disclosed correlation between that function and a structure that is sufficiently known or disclosed,” the written description requirement may be met).
With respect to the recitation an engineered αβ T cell receptor (TCR) which does not comprise both TCTα chain and the TCRβ chain of the TCR, the Examiner notes that engineering synthetic TCRs for increased tumor/viral antigen recognition is complicated by the risk of introducing cross-reactivity and by the poor correlation that can exist between binding affinity and activity of TCRs in response to antigen (peptide-MHC). The TCR specific for the tumor antigen MAGE-A3 used the CDRs of both its alpha(α) and beta (β) chains to recognize peptide-MHC complexes.
It is unlikely that TCR which may contain less than the required TCRαβ chains have the required binding function. The specification provides no direction or guidance regarding how to produce specific TCR as broadly defined by the claims. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone.
It is noted that A3A (SEQ ID NO: 2) TCR that showed off target cross-reactivity and toxicity.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
17. Claims 1-6 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 an engineered αβ T-cell receptor (TCR) specific for human MAGE-A3 comprising a beta chain of SEQ ID NO: 16 and an alpha chain of SEQ ID NO: 2-15 or a mature version thereof, does not reasonably provide enablement for engineered αβ T cell receptor (TCR) specific for human MAGE-A3 recited in claims 1-6. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 1 encompasses a broad genus of human MAGE-A3 comprising a genus of at least one amino acid modification in the alpha (α) chain of SEQ ID NO: 1 at D28, A30, I51, Q52, S53 and/or S54 to enhance target activation potency and lacking the TCRβ chain. That is claim 1 encompasses up to 6 amino acids modification and since there are 20 naturally occurring amino acids, then the claim encompasses up to 206 = 64,000,000 different mutations in the TCRα chain and lacking the TCRβ.
Claim 4 encompasses a combination of up to 38,760 modifications in TCRα chain of SEQ ID NO: 1 and lacks the TCRβ chain.
Claim 5 encompasses unknown variants of the already modified TCRα chains of SEQ ID NOs: 2-15 and lacking the TCRβ chain.
Claim 6 encompasses up to 5% modification in the already modified TCRα chains of SEQ ID NO: 2-15 and lacking the TCRβ chain. That is 5% of 274 amino acids of SEQ ID NOs: 2-15 is ~14 amino acids to be modified. That is 2014 which is 163,840,000,000,000 (163.84 trillion modification) in each SEQ ID NO.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The claims are directed to a broad class of TCR was that the class was defined by its function—the ability to enhance target activation potency and treat MAGE-A3 expressing cancer. However, the specification did not give the skilled in the art enough information to choose candidate TCRs from the 64,000,000 of options and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
The specification discloses only 14 species of MAGE TCR mutants, SEQ ID NO:2-15; while the claims are directed to a genus of 64,000,000 MAGE TCR mutants.
In Sanofi-Aventisub, the Federal Circuit relied on its prior precedential opinions when determining whether the full scope of a genus was enabled. These decisions included McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091 (Fed. Cir. 2020) (hereafter McRO); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380 (Fed. Cir. 2013) (hereafter Wyeth); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019) (hereafter Enzo); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149 (Fed. Cir. 2019) (hereafter Idenix).
The Federal Circuit, citing McRO, provided guidance on the application of enablement to genus claims, holding that “[a]lthough a specification does not need to describe how to make and use every possible variant of the claimed invention, when a range is claimed, there must be reasonable enablement of the scope of the range.” Sanofi-Aventisub, 987 F.3d at 1085 (internal quotations omitted). Additionally, the Federal Circuit characterized Wyeth as holding “that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality.” Id. at 1086. Similarly, the Federal Circuit characterized Enzo as holding “that the specification failed to teach one of skill in the art whether the many embodiments of the broad claims would exhibit that required functionality.” Id. Finally, the Federal Circuit characterized Idenix as affirming “the district court's determination that the claims had both structural and functional limitations, and that undue experimentation would have been required to synthesize and screen the billions of possible compounds because, given a lack of guidance across that full scope, finding functional compounds would be akin to finding a `needle in a haystack.' ” Id.
This case is akin to the issue in Sanofi-Aventisub, the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a `vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. In the instant case, the specification discloses only two species that performed the claimed function by their amino acid sequences, with the claimed genus of 9,905 different anti-hANGPTL3 antibodies. The instant claims are directed to a class of anti-hANGPTL3 antibodies that included “a `vast' number of additional antibodies” that the instant specification fails to describe their amino acid sequences.
The scope of the instant claims encompassed 64,000,000 MAGE TCR mutants and that it was necessary to first generate and then screen each candidate to determine whether it met the functional limitations. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the 14 MAGE TCR mutants of SEQ ID NO: 2-15 they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
18. No claim is allowed.
19. SEQ ID NOs: 2-15 are free from prior art.
20. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
Xiang Zhao et al. Tuning T cell receptor sensitivity through catch bond engineering. Science 376, eabl5282 (2022)
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.
August 10, 2026 /MAHER M HADDAD/ Primary Examiner, Art Unit 1644
Prosecution Insights