Notice of Pre-AIA or AIA Status
1. 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
Election/Restrictions
2. Applicant’s election without traverse of Group I, claims 27-31, 33, 34 (in part) and 35-39 in the reply filed on 12 May 2026 is acknowledged. Applicant’s election of antibody 16A08, having a variable heavy chain of SEQ ID NO: 47 (CDRs of SEQ ID NOs: 112, 113 and 114) and a variable light chain of SEQ ID NO: 48 (CDRs: SEQ ID NOs: 184, 185 and 186), as the species of antibody that binds an isoform of STIM1, in the reply filed on 12 May 2026 is also acknowledged. Claims 32 and 40-49 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12 May 2026.
Status of Application, Amendments, and/or Claims
3. The Response filed on 12 May 2026 has been entered in full. Claims 32 and 40-49 have been withdrawn as discussed supra. Therefore, claims 27-49 are pending, and claims 27-31 and 33-39 are the subject of this Office Action.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 26 July 2023 has been considered by the Examiner.
Specification
5. The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: ANTIBODIES WHICH BIND STIM1 SPLICING VARIANT AND USES THEREOF.
Appropriate correction is required.
Improper Markush
6. Claims 28-29, 34, and 37-38 are rejected (and dependent claims 36 and 39 are also rejected) on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
7. In the instant case, the Markush grouping of antibodies which bind an isoform of STIM1 recited in claims 28-29 and 37-38, and the antibodies and probes/primers recited in claim 34, is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the various antibodies and the probes/primers have different amino acid or nucleic acid sequences and/or different chemical structures, and thus share no structural similarity. Therefore, there is no substantial common structural feature and a common use that flows from the substantial structural feature.
8. To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
9. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
10. Claims 34 and 36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
11. Claim 34 is rejected as being indefinite for reciting the limitation “a probe or primer specific to a coding sequence for the isoform of STIM1 of SEQ ID NO: 1.” Since claim 34 depends from claim 33 which recites detecting the protein of SEQ ID NO: 1, it isn’t clear what additional elements are required for “a probe or primer specific to a coding sequence” (i.e., a nucleic acid sequence) to detect the protein of SEQ ID NO: 1, and therefore the claim is indefinite.
12. Claim 36 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: how detecting an isoform of STIM1 of SEQ ID NO: 1 relates to the prognosis of a subject having a cancer or a myelodysplastic syndrome.
Claim Rejections - 35 USC § 112 (Written Description)
13. The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
14. Claims 27, 30-31 and 33-36 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.
15. The U.S. Court of Appeals for the Federal Circuit recently reaffirmed, in an en banc decision, that the written description requirement for a genus may be satisfied either by (i) the disclosure of a representative number of species falling within the scope of the genus or (ii) structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus. Ariad Pharmaceuticals', Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350, 94 U.S.P.Q.2d 1161, 1171 (en banc) (Fed. Cir. 2010), citing Regents" of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568-69, 43 U.S.P.Q.2d 1398, 1406 (Fed. Cir. 1997).
16. The representative ways of satisfying the written description requirement as set out by the Federal Circuit in Ariad Pharmaceuticals comport with statements set out in the USPTO's Manual of Patent Examining Procedure (M.P.E.P.). In particular, the M.P.E.P. provides that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species of relevant identifying characteristics. M.P.E.P. § 2163, II, A, 3, (a), (ii).
17. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163.
18. In the instant case, the claims are drawn quite broadly to an antibody specific to an isoform of STIM1 comprising SEQ ID NO: 1, which differentially binds to said isoform in comparison to an isoform of STIM1 comprising SEQ ID NO: 5, or an antigen-binding fragment thereof. The claims also recite wherein the antibody is a chimeric, humanized or human antibody; or wherein the antibody competes with an antibody selected from the group of 1E05, 1F02, 2F12, 4B05, 8E11, 15G09, 15H01 and 16A08 for binding to a polypeptide comprising SEQ ID NO: 1 or a fragment thereof, said fragment comprising SEQ ID NO: 3. The claims also an in vitro method for detecting an isoform of STIM1 of SEQ ID NO: 1 comprising contacting a sample with a detection means specific to the isoform of STIM1 of SEQ ID NO: 1 and detecting the presence of the isoform of STIM1 of SEQ ID NO: 1; an in vitro method for detecting a cancer or a myelodysplastic syndrome or a susceptibility to develop a cancer or a myelodysplastic syndrome in a subject, wherein the method comprises detecting an isoform of STIM1 of SEQ ID NO: 1 in a sample from said subject by said method, or an in vitro method for providing information on a prognosis of a subject having a cancer or a myelodysplastic syndrome, wherein the method comprises detecting an isoform of STIM1 of SEQ ID NO: 1 in a sample from said subject by said method. The claims also recite wherein the detection means is an antibody specific to an isoform of STIM1 comprising SEQ ID NO: 1, which differentially binds to said isoform in comparison to an isoform of STIM1 comprising SEQ ID NO: 5, or an antigen-binding fragment thereof. Thus, the claims have been broadly interpreted by the Examiner as reading upon an extremely large genus of antibodies that are defined only by antigen to which they bind.
19. For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
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.”), see MPEP 2163.IIAii.
20. Several recent court decisions speak to the notion that claiming a molecule with unknowable structural heterogeneity solely by reciting its function is not sufficient to establish possession of a genus so claimed. For example, quoting Eli Lilly the court states in Ariad, 598 F.3d at 1350: "[A] sufficient description of a genus requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." (quoting Eli Lilly, 119 F.3d at 1568-69).
21. A "representative number of species" means that the species which are 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.").
22. In the instant case, the claims encompass in their breadth antibodies and antigen-binding binding fragments thereof that are specific to an isoform of STIM1 comprising SEQ ID NO: 1, which differentially binds to said isoform in comparison to an isoform of STIM1 comprising SEQ ID NO: 5, or competes with an antibody selected from the group of 1E05, 1F02, 2F12, 4B05, 8E11, 15G09, 15H01 and 16A08 for binding to a polypeptide comprising SEQ ID NO: 1 or a fragment thereof, said fragment comprising SEQ ID NO: 3.
23. Given the exceedingly large genus of antibodies and fragments encompassed by the claims, one of skill in the art cannot possibly envision the structures contained within this genus that will have the property of being specific to an isoform of STIM1 comprising SEQ ID NO: 1, which differentially binds to said isoform in comparison to an isoform of STIM1 comprising SEQ ID NO: 5, or competes with an antibody selected from the group of 1E05, 1F02, 2F12, 4B05, 8E11, 15G09, 15H01 and 16A08 for binding to a polypeptide comprising SEQ ID NO: 1 or a fragment thereof, said fragment comprising SEQ ID NO: 3. Moreover, the Specification does not describe any human antibodies with the property of being specific to an isoform of STIM1 comprising SEQ ID NO: 1.
24. In contrast to the breadth of the claims. the specification discloses particular antibodies that are defined by particular amino acid sequence for variable heavy chain variable light chain regions as well as the particular amino acid sequences for the three CDR sequences from both the VH and VL domains, which are disclosed as specifically binding to an isoform of STIM1 comprising SEQ ID NO: 1 (See pp. 46-49, for example). However, 8 species of antibodies which specifically bind to an isoform of STIM1 comprising SEQ ID NO: 1 is not representative of the unlimited breadth of the claimed antibodies and fragments recited in the claims.
25. It is well established in the art that the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff, et al. (PNAS, 1982. Vol. 79, page 1979). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. MacCallum, et al. (J. Mol. Biol., 262:732-745) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column). De Pascalis, et al. (Journal of Immunology, 2002. 169:3076-3084) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right column). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left column).
26. The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AlA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
27. While generically the structure of antibodies is known, the structure of the presently recited antibodies to be produced and screened in the instant method can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” (See p. 8, lines 3-5 of WO 2009/033743 A1). Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of claimed antibodies.
28. 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. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
29. An adequate written description of a chemical invention requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”). See MPEP 2163IIA3(a).
30. Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus of antibodies and antigen-binding binding fragments thereof that bind to an isoform of STIM1 comprising SEQ ID NO: 1 encompassed in the breadth of the instant claims.
31. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that in order to satisfy the written description requirement, “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). As discussed above, the skilled artisan cannot envision the detailed structure of the encompassed genus of therapeutic antibodies and antigen-binding binding fragments thereof that bind to an epitope in the B2 or C domain of human NRP2, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
32. Without a correlation between structure and function, the claims do little more than define the claimed invention by function, which 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 genus does, rather than what it is").
33. Therefore, only an antibody comprising (1) a heavy chain variable domain having the amino acid sequence SEQ ID NO: 47 and a light chain variable domain having the amino acid sequence SEQ ID NO: 48, (2) antibodies comprising the full complement of 6 CDRs from said variable domains in their proper order (i.e., heavy chain CDR1, CDR2, CDR3 comprising amino acid sequences SEQ ID NO:112, SEQ ID NO: 113 and SEQ ID NO: 114, respectively, and light chain CDR1, CDR3, CDR3 comprising amino acid sequences SEQ ID NO: 184, SEQ ID NO: 185 and SEQ ID NO: 186, respectively), but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 112 (Scope of Enablement)
34. Claim 36 is 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
35. The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
36. The claim is drawn to an in vitro method for providing information on a prognosis of a subject having a cancer or a myelodysplastic syndrome, wherein the method comprises detecting an isoform of STIM1 of SEQ ID NO: 1 in a sample from said subject, wherein the presence of the isoform of STIM1 of SEQ ID NO: 1 being indicative of the prognosis of the subject. However, in view of the omission of essential steps set forth under 35 U.S.C. § 112(b) supra, the claims fail to teach how to achieve the proposed method.
37. Specifically, since the claims are missing the essential steps of how detecting an isoform of STIM1 of SEQ ID NO: 1 relates to the prognosis of a subject having a cancer or a myelodysplastic syndrome, the method as claimed is not enabled. Furthermore, while the Specification discloses that the presence of the STIM1 isoform is indicative of a number of cancers, particular those associated with SF3B1 mutations, there is no direction or guidance regarding the presence of the STIM1 isoform in a sample taken from a subject and the expected outcome or progression of a cancer or a myelodysplastic syndrome.
38. Thus, in view of the omission of essential steps and the lack of direction and guidance regarding the assays, the instant specification is not found to be enabling for the methods as presently claimed. It would require undue experimentation and making a substantial inventive contribution for the skilled artisan to discover how to make and/or use the Applicants' invention as currently claimed.
Summary
39. No claim is allowed.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jon M. Lockard whose telephone number is (571) 272-2717. The examiner can normally be reached on Monday through Friday, 8:00 AM to 4:30 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached on (571) 272-2911. The fax number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JON M LOCKARD/
Examiner, Art Unit 1647
June 27, 2026
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