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 .
Claim Status
Applicant’s amendments and remarks, filed 10/30/2025, are acknowledged.
Claims 1-51 are canceled.
Claims 52-56, 59, and 66-67 are amended.
Claims 69-71 are new.
Claims 52-71 are pending.
Claims 57, 58, and 61-63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 06/17/2025.
Claims 60 and 64-66 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 06/17/2025.
As such, claims 52-56, 59, and 67-71 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/26/2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections
The drawings, specification, and sequence disclosure objections are withdrawn in part. Issues regarding minor informalities, trademarks/names, and missing incorporation by reference paragraph have been sufficiently addressed through amendments to the drawings and specification on 10/30/2025.
The claim objections are withdrawn. Issues regarding minor informalities have been sufficiently addressed through amendments to the claims filed on 10/30/2025.
Withdrawn Rejections
Applicant’s arguments, see pages 21 and 22, filed 10/30/2025, with respect to claim 59 rejected under 35 USC 112(d) as allegedly being of improper dependent form have been fully considered and are persuasive. The issue regarding improper dependent subject matter have been sufficiently addressed through amendments to the claim(s). As such, the rejection under 35 USC 112(d) is withdrawn.
Applicant’s arguments, see page 22, filed 10/30/2025, with respect to claims 52-56, 59, and 67-68 rejected under 35 USC 112(b) as allegedly being indefinite have been fully considered and are persuasive in part. The issue regarding the claims comprising indefinite language have been sufficiently addressed through amendments to the claims. Specifically, the following rejections are withdrawn:
Claims 52, 54-56, 59, and 67 comprising the phrases "preferably”, “more preferably”, “even more preferably”, and/or “most preferably”;
Claims 52-56, 59, and 67 comprising the phrase “optionally”;
Claims 52, 55, 56, and 67 recite the broad recitation “at least 80%”, and the claims also recite “at least 90%” and/or “100% sequence identity” which is the narrower statement of the range/limitation;
Claims 52, 56, and 67 recite the broad recitation “an integer between 1 and 15”, and the claims also recite “between 1 and 10”, “between 1 and 5” and “between 3 and 5” which is the narrower statement of the range/limitation;
Claims 52, 56, and 67 recite the broad recitation “n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15”, and the claims also recite “n is optionally an integer between 0 and 2” which is the narrower statement of the range/limitation;
Claims 53 and 54 recite “and wherein optionally the spacer domain comprises one or more IgG3 middle hinge domain repeat motifs”;
Claim 54 is unclear because it appears to repeat the language of “the linker comprises one or more IgG3 middle hinge domain repeat motifs”;
Claim 54 recites the broad recitation “a T-cell receptor (TCR)” and “a B-cell receptor (BCR)”, and the claim also recites “a recombinant TCR” and “a recombinant BCR”, respectively, which is the narrower statement of the range/limitation;
Claim 55 recites the broad recitation “I) the first domain comprises a heavy chain variable domain”, and the claim also recites “III) the first domain comprises a heavy chain variable domain, and the second domain comprises a light chain variable domain; IV) the first domain comprises a heavy chain variable domain, and the second domain comprises a heavy chain variable domain” which is the narrower statement of the range/limitation;
Claim 55 recites the broad recitation “II) the first domain comprises a light chain variable domain”, and the claim also recites “V) the first domain comprises a light chain variable domain, and the second domain comprises a light chain variable domain” which is the narrower statement of the range/limitation;
Claim 55 parts A-I fails to add a conjunction such as “and” in all subparts (i), and therefore it is unclear if the heavy and light chain are alternatives or both required;
Claims 56 and 67 recite the broad recitation “at least two”, and the claim also recites “at least three” which is the narrower statement of the range/limitation;
Claims 56 and 67 recite the broad recitation “IgG3 middle hinge domain repeat motif… n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15” (see the second II), and the claims also recite “the IgG3 middle hinge domain repeat motif 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times” (see the second III) which is the narrower statement of the range/limitation; and,
Claim 59 recites the broad recitation “leukemia or lymphoma”, and the claim also recites “acute myeloid leukemia…non-Hodgkin lymphoma, Burkitt’s lymphoma, mantle cell lymphoma, acute lympho9blastic leukemia, chronic lymphocytic leukemia, or diffuse large B cell lymphoma” which is the narrower statement of the range/limitation.
As such, the above rejections under 35 USC 112(b) are withdrawn.
The rejection of claims 52-56, 59, and 67-68 under 35 USC 112(a) as allegedly failing to comply with the written description requirement is modified in favor of the new limitations added in the amendment filed 10/30/2025. Applicant’s arguments, see pages 22 and 23, filed 10/30/2025, with respect to claims 52-56, 59, and 67-68 rejected under 35 USC 112(a) have been fully considered.
The provisional rejection of claims 52-56 and 59 on the grounds of nonstatutory double patenting is modified in favor of the new limitations added in the amendment filed 10/30/2025. Applicant’s arguments, see page 27, filed 10/30/2025, with respect to claims 52-56 and 59 provisionally rejected have been fully considered.
Maintained Objections and Rejections
Information Disclosure Statement
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.
Response to Arguments
Applicant has not made any remarks regarding the listing of references in the specification. As such, this objection is maintained.
Drawings
The drawings are objected to because Figure 18B comprises an asterisk but the drawing nor the specification indicate what the asterisk means.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Applicant’s Arguments
Applicant indicates that the Figure legend of Figure 18 was updated to indicate that the asterisk indicates statistical significance (see page 20 of the Remarks filed 10/30/2025).
Response to Arguments
Applicant's arguments filed 10/30/2025 have been fully considered but they are not persuasive. Examiner acknowledges that substitute Figures 1 and 19 were filed to overcome the objections; however, a substitute Figure 18B was not filed. As such, the objection of Figure 18B is maintained.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 55 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 55 recites “IV) the first domain comprises a heavy chain variable domain, and the second domain comprises a heavy chain variable domain; or V) the first domain comprises a light chain variable domain, and the second domain comprises a light chain variable domain”. It is unclear if the second domain is different from the first domain (i.e., the first domain and the second domain comprise the same sequence, or are two different sequences). As such, claim 55 and its dependent claims are rejected.
Applicant’s Arguments
Application states that the 112(b) rejections are believed to have been addressed by the amendment to the claims (see page 22 of the Remarks filed on 10/30/2025).
Response to Arguments
Applicant's arguments filed 10/30/2025 have been fully considered but they are not persuasive. Examiner acknowledges the amendments to the claim; however, the amendments do not overcome the rejection because it remains unclear if the second domain is different from the first domain (i.e., the first domain and the second domain comprise the same sequence, or are two different sequences). Applicant has not made any arguments or amendments that specifically address this limitation. As such, the 112(b) rejection of claim 55 is maintained.
Claim Rejections - 35 USC § 112(a) Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 52-56, 59, and 67-71 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. 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 “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 52 is drawn to an immunoreceptor, comprising one or more IgG3 middle hinge repeat domain motifs, wherein the immunoreceptor does not comprise an IgG3 CH2 and/or CH3 domain, wherein the immunoreceptor comprises an amino acid sequence which has at least 90% sequence identity with the amino acid sequence of [A-Bn], wherein A is the amino acid sequence of SEQ ID NO: 2; B is said IgG3 middle hinge domain repeat motif, wherein said motif has the amino acid sequence of SEQ ID NO: 1; and n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
Claim 53 is drawn to the immunoreceptor according to claim 52, wherein the immunoreceptor is a chimeric antigen receptor (CAR) comprising: an extracellular antigen-binding domain, a spacer domain, a transmembrane domain, and an intracellular signaling domain; wherein the spacer domain is located between the extracellular antigen-binding domain and the transmembrane domain, and wherein the spacer domain comprises the one or more IgG3 middle hinge domain repeat motifs.
Claim 54 is drawn to the immunoreceptor according to claim 53, comprising an extracellular antigen-binding domain comprising: a first domain, a linker, and, a second domain.
Claim 55 is drawn to the immunoreceptor according to claim 54, wherein the immunoreceptor comprises the extracellular antigen-binding domain, wherein I) the first domain comprises a heavy chain variable domain; II) the first domain comprises a light chain variable domain; III) the first domain comprises a heavy chain variable domain, and the second domain comprises a light chain variable domain; IV) the first domain comprises a heavy chain variable domain, and the second domain comprises a heavy chain variable domain; or V) the first domain comprises a light chain variable domain, and the second domain comprises a light chain variable domain, and/or wherein the immunoreceptor comprises the extracellular antigen-binding domain, said antigen-binding domain comprising the first domain, linker, and second domain, which are part of a single chain variable fragment (scFv).
Claim 56 is drawn to the immunoreceptor according to claim 52, wherein the immunoreceptor is a chimeric antigen receptor (CAR), wherein the one or more IgG3 middle hinge domain repeat motifs I) are from a human IgG3 middle hinge; and/or II) consist of the amino acid sequence of SEQ ID NO: 1; and/or III) have reduced immunogenicity compared to repeats of an IgG1 hinge domain and/or an IgG4 hinge domain.
Claim 59 is drawn to a method of treating a cancer, an autoimmune disease, an infectious disease or a degenerative disease comprising administering the immunoreceptor according to claim 52 to a patient.
Claim 67 is drawn to a bispecific antibody, comprising one or more IgG3 middle hinge repeat domain motifs, wherein the one or more IgG3 middle hinge domain repeat motifs I) are from a human IgG3 middle hinge; and/or II) consist of the amino acid sequence of SEQ ID NO: 1; and/or III) have reduced immunogenicity compared to repeats of an IgG 1 hinge domain and/or an IgG4 hinge domain; and/or wherein the bispecific antibody: I) does not comprise all or part of the sequence of the lower hinge domain of a human IgG3 hinge domain; II) comprises an amino acid sequence which has 100% sequence identity with the amino acid sequence of [A-Bn], wherein A is the amino acid sequence of SEQ ID NO: 2; B is said IgG3 middle hinge domain repeat motif, wherein said motif has the amino acid sequence of SEQ ID NO: 1; and n is selected from the group consisting of 0, 1, 2,3,4,5,6, 7, 8, 9, and 10; III) comprises the IgG3 middle hinge domain repeat motif 1, 2, 3, 4, 5, 6, 7,8, 9 or 10 times; and/or IV) has reduced immunogenicity compared to a second bispecific antibody which differs from the first bispecific antibody in that it does not comprise said one or more IgG3 middle hinge domain repeat; and/or wherein the bispecific antibody comprises at least two IgG3 middle hinge repeat domain motifs.
Claim 68 is drawn to the immunoreceptor of claim 52, wherein the IgG3 middle hinge repeat domain motif is not a mouse IgG3 middle hinge repeat domain.
Claim 69 is drawn to the immunoreceptor according to claim 54, wherein the linker is located between the first domain and the second domain, and wherein the linker comprises the one or more IgG3 middle hinge domain repeat motifs; and/or wherein the spacer domain comprises the one or more IgG3 middle hinge domain repeat motifs, and/or wherein the linker comprised in the extracellular antigen-binding domain comprises the one.
Claim 70 is drawn to the immunoreceptor according to claim 55, wherein the scFv comprises, as heavy/light chain variable sequences comprised in the first/second domain, heavy/light chain variable sequences of scFvs specific for one of the following antigens: A) CD19; B) CD20;C) Receptor tyrosine kinase like orphan receptor 1 (ROR1); D) Receptor tyrosine kinase like orphan receptor 2 (ROR2); E) SLAM family member 7 (SLAMF7); F) Fms related receptor tyrosine kinase 3 (FLT3); G) Siglec-6; H) αvβ3 integrin; or I) B-cell maturation antigen (BCMA): and/or wherein the immunoreceptor comprises the extracellular antigen-binding domain, said antigen- binding domain comprising an scFv: L) specific to CD19; II) specific to CD20; III.) specific to ROR1; IV.) specific to ROR2; V.) specific to SLAMF7; VI.) specific to FLT3; VII.) specific to Siglec-6; VIII.) specific to αvβ3 integrin; or IX.) specific to BCMA.
Claim 71 is drawn to the immunoreceptor of claim 52, wherein the immunoreceptor comprises an amino acid sequence which has 100% sequence identity with the amino acid sequence of [A-Bn].
The specification disclose of generating an IgG3 hinge-based CAR spacer library, in which scFv and transmembrane domain are connected by variants of the human IgG3 hinge domain; which naturally consists of upper hinge (12 aa, ELKTPLGDTTHT, SEQ ID NO: 2), middle hinge (50 aa, CPRCP, SEQ ID NO: 59 + 3 repeats of EPKSCDTPPPCPRCP, SEQ ID NO: 1) and lower hinge (8 aa, APELLGGP, SEQ ID NO: 60), leading to a total spacer size of 70 aa for this wild-type spacer termed IgG3_UMLH (upper, middle and lower hinge) (see Example 1). From that, variants were constructed consisting of upper hinge, the start of the middle hinge (CPRCP, SEQ ID NO: 59) and 0-10 copies of the EPKSCDTPPPCPRCP motif (SEQ ID NO: 1) leading to spacer domains spanning 17 to 167 aa in 15 aa steps named IgG3_MiH0 to IgG3_MiH10 (see Fig. 1).
Examples 2-6 demonstrate experiments testing five IgG3 hinge variants (IgG3_MiH1, IgG3_MiH2, IgG3_MiH3, IgG3_MiH4 and IgG3_MiH5) and comparing them to an IgG4 construct. Example 2 indicates that all variants showed a comparably strong specific proliferation upon encounter of CD19-expressing target cells; variants IgG3_MiH1 and IgG3_MiH2 displayed a pronounced cytotoxic effect similar to that of the IgG4 CAR while cytolysis was reduced for longer IgG3 variants. Example 3 indicates that the IgG3_MiH1 variant comprising the 4-2 scFv and IgG4 showed comparable proliferation, cytotoxicity and cytokine secretion upon antigen encounter, whereas IgG3_MiH1 comprising the R11 scFv did not induce antigen-specific proliferation or cytotoxic response upon encounter of ROR1+ target cells while all other variants led to effective tumor cell lysis with IgG3_MiH2, IgG3_MiH3, and IgG3_MiH4 being as effective as the IgG4 variant. The inability of IgG3_MiH1 to induce antigen-dependent T cell effector functions is caused by a spacer length insufficient to reach the epitope (see pg. 133). Example 4 demonstrates that the shortest IgG3 variant (IgG3_MiH1) showed the best proliferation upon antigen encounter, thereby surpassing the IgG4 variant by a wide margin, while longer IgG3 variants proliferated much less (see Figure 5A). Variants IgG3_MiH2 and IgG3_MiH3 led (together with the IgG4 variant) to best cytotoxic effects, while IgG3_MiH1, IgG3_MiH4, and IgG3_MiH5 exhibited far less cytotoxicity (see Figure 5B). IgG3_MiH1 and IgG3_MiH2 showed comparable amounts of IFNγ to be released while the longer IgG3 variants secreted less (see Figure 5C). Example 5 demonstrates that the shortest spacer variant investigated (IgG3_MiH1) showed the highest level of antigen-specific proliferation, outperforming the IgG4 variant equipped with a long IgG4-based spacer (hinge-CH2-CH3). Even though none of the IgG3 variants could reach the level of IgG4 for killing of the SLAMF7 expressing myeloma cell line MM.1S, IgG3 variants equipped with 1, 2, or 3 IgG3_MiH repeats led to profound cytolysis; however, the IgG3_MiH1 IgG3 variant led to the highest secretion with IgG3_MiH2 equaling the IgG4 variant right behind (see Figure 6). Example 6 demonstrates that IgG3_MiH1 outperforms the IgG4 variant (IgG4 long) in specific proliferation and cytokine secretion (IFNγ) encounter of the antigen, while both variants display equal cytotoxic capacity.
In an in vivo experiment, the IgG3_MiH1 variant and the IgG4 CAR led to complete eradication of the CD19+ Raji tumor cells; though tumor cells eventually grew out in all mice, the IgG3_MiH1 variant delayed this outgrow and led to significantly prolonged survival rate as compared to the IgG4 variant (see Figure 8A-B). Another mouse experiment was performed applying ROR1-specfiic CAR T cells equipped with the R11 scFv in mice engrafted with Jeko-1 for 7d; while neither the IgG4 spacer variant, nor IgG3 variants IgG3_MiH1 and IgG3_MiH4 influenced Jeko-1 tumor growth and survival of the treated animals, IgG3_MiH3 and especially IgG3_MiH2 led to attenuated tumor growth and prolonged animal survival (see Figure 9).
Lastly, Example 18 demonstrates in vitro cytotoxic function of additional advanced IgG3 format CAR T cells and comparison to CD8α format. In this example, the cytotoxic capacity of T cells equipped with optimized IgG3 variants of additional CARs targeting ROR1 (4-2 scFv), FLT3 (4G8 and BV10) and Siglec-6 (JML-1 scFv, comprising SEQ ID Nos: 49 and 50), and compared them to CARs with the same scFvs constructed in the widely applied CD8α setup (CD8α hinge and transmembrane domains). All advanced IgG3 versions exhibited a significantly enhanced cytotoxic potential as compared to CD8α versions (see Figure 22A-D).
However, the specification fails to disclose that Applicant was in possession of the large genera of immunoreceptors and bispecific antibodies as claimed. Specifically, the claims describe the structure of these immunoreceptors and bispecific antibodies by function (e.g., claim 53 recites “an extracellular domain”, “an intracellular signaling domain”, binding a specific antigen, etc.) and/or partial structure (e.g., “comprises an amino acid sequence which has at least 90% sequence identity with the amino acid sequence of [A-Bn], wherein A is the amino acid sequence of SEQ ID NO: 2; B is said IgG3 middle hinge domain repeat motif, wherein said motif has the amino acid sequence of SEQ ID NO: 1…”). Additionally, claim 70 recites several species of variable heavy and light chains that target different antigens; however, the claim alternatively doesn’t define the binding regions.
Although the specification discloses of CAR variants consisting of upper hinge (SEQ ID NO: 2), the start of the middle hinge (CPRCP, SEQ ID NO: 59) and 0-10 copies of the EPKSCDTPPPCPRCP motif (SEQ ID NO: 1) that target CD19, ROR1, ROR2, FLT3, or Siglec-5, the claims are not limited to these immunoreceptors, and are inclusive of any immunoreceptors and bispecific antibodies comprising at least 90% variability for the hinge domain and the extracellular antigen-binding domain. This indicates that there are thousands, if not millions, of possible immunoreceptors and bispecific antibodies encompassed by the claims. Thus, the claims encompass a vast genus of immunoreceptors and bispecific antibodies that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of immunoreceptors and bispecific antibodies because, inter alia, the specification does not disclose a correlation between the necessary structure of the immunoreceptor or bispecific antibody and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Further, the specification fails to provide method steps that result in treating cancer, autoimmune disease, infectious disease, or degenerative disease patients. Although the term antibody does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies/immunoreceptors and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of immunoreceptors/antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of bispecific antibodies or immunoreceptors. The disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; 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.") (MPEP 2163).
The instant claims do not fully describe the structure of the immunoreceptor or bispecific antibodies to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of bispecific antibodies or immunoreceptors, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous bispecific antibodies or immunoreceptors had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of bispecific antibodies or immunoreceptors claimed only by a partial structure and functional characteristic(s). Thus the bispecific antibodies or immunoreceptors described by the instant claims encompasses an overly broad genus, the structure of secondary antigen or therapeutic agent, and the functional outcome.
CAR T cell therapy is unpredictable, and recent studies demonstrate that many aspects of CAR signaling are unique, distinct from endogenous TCR signaling, and potentially even distinct among various CAR constructs (see e.g. Lindner et al. (Sci Adv. 2020 May 20;6(21):eaaz3223); previously submitted with the Office Action mailed 07/30/2025). Thus, rigorous and comprehensive proteomic investigations are required for rational engineering of improved CARs (see e.g. abstract). CAR T cell therapy has transformed many aspects of clinical and translational oncology, and the successes achieved to date have led to a rapid expansion of clinical and basic science research efforts in this area (see e.g. page 6, left column, second paragraph). However, this explosion has, in many ways, outpaced fundamental investigations into how these receptors work, which threatens to limit our ability to improve upon current designs in an optimal fashion (see e.g. page 6, left column, second paragraph). Characteristics such as CAR avidity, scFv affinity, antigen-binding domain structure and size, hinge/spacer region length and design, and transmembrane domain choice all affect the kinetics and dynamics of signaling pathway activation, just as choice of cytoplasmic signaling moieties affects the specific pathways that are proximally activated (see e.g. page 6, left column, fourth paragraph).
CAR-T cell therapies have been approved by the FDA to treat some kinds of leukemias and lymphomas, as well as multiple myeloma (see page 13, American Cancer Society “CAR T-cell therapy and its side effects”, downloaded from https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/car-t-cell1.html on 11/13/24; last revised November 11, 2024; previously submitted with the Office Action mailed 07/30/2025). At least six different therapies have been approved for use by the US Food and Drug Administration (FDA) in these cancers (see p. 13, American Cancer Society, and entire reference section).
According to Guzman et al (Current Oncology Reports (2023) 25:479–489; previously submitted with the Office Action mailed 07/30/2025), CAR-T therapy has shown success in treating hematological malignancies (see e.g. page 480, left column, second paragraph). Despite revolutionary progress in blood cancers, equivalent success has yet to be duplicated in solid tumor malignancies (see e.g. page 480, left column, second paragraph). Significant developments such as allogeneic or “of-the-shelf” CAR-T cells, which involve T cells from a donor's circulating blood, have attempted to improve success. However, solid tumors present unique challenges, such as a hostile tumor microenvironment (TME) and heterogeneous antigen expression that hinder similar advancements (see e.g. page 480, left column, second paragraph). A central difference between solid tumors and hematological cancers is the intricacy in detecting a perfect target antigen (see e.g. page 480, left column, third paragraph). While target heterogeneity exists in blood cancers, these disorders more commonly tend to express individual markers (i.e., B-cell marker CD19) (see e.g. page 480, left column, third paragraph). Additionally, solid tumors more often have tumor-associated antigens (TAA), where this antigen is highly expressed on the tumor itself but also at low levels in normal tissues. Furthermore, solid tumors display TAA heterogeneity between tumor types (primary vs. metastatic) and patients with the same cancer (see e.g. page 480, left column, third paragraph) Consequently, a significant roadblock is designing a proper CAR-T cell with the capability of finding an ideal target antigen in solid tumors (see e.g. page 481, right column, second paragraph to page 482, left column, first paragraph). Once a CAR-T cell invades the endothelial barrier, it must continue to survive and persist in the inhospitable tumor microenvironment (TME) (see e.g. page 481, right column, second paragraph to page 482, left column, first paragraph). The TME presents a myriad of obstacles to CAR-T therapy, including the tumor stroma composed of suppressive cell types such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) and hypoxic conditions that hamper its execution (see e.g. page 481, right column, second paragraph to page 482, left column, first paragraph). Further, on-target off-tumor toxicity can be detrimental when CAR-T cells are directed to attack a tumor antigen that is also present in normal tissues (see e.g. page 482, left column, fourth paragraph). These data suggest that treatment of solid tumors or prevention of cancer with CAR-T cell therapy would be highly unpredictable.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that 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.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of bispecific antibodies by the functions of the IgG3 middle hinge repeat domain motifs. Additionally, the claims attempt to define the genus of immunoreceptors by the vast functions recited in claims 55 and 70. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
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.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed bispecific antibodies or immunoreceptors, 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 for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed bispecific antibodies, the functional characteristics of antibodies (including binding specificity and affinity) are dictated on their structure. Amino acid sequence and conformation 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. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416; previously submitted with the Office Action mailed 07/30/2025) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2; previously submitted with the Office Action mailed 07/30/2025), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies and immunoreceptors that have specific required functions. In the instant application, neither the art nor the specification provides a sufficient representative number of antibodies/therapeutic agents or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed proteins and peptides (i.e., the bispecific antibodies and immunoreceptors), protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9; previously submitted with the Office Action mailed 07/30/2025), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990; previously submitted with the Office Action mailed 07/30/2025) who teach that replacement of a single lysine residue at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988; previously submitted with the Office Action mailed 07/30/2025) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98; previously submitted with the Office Action mailed 07/30/2025) teach that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400; previously submitted with the Office Action mailed 07/30/2025) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668; previously submitted with the Office Action mailed 07/30/2025), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937; previously submitted with the Office Action mailed 07/30/2025). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed immunoreceptors and bispecific antibodies could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of proteins, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all immunoreceptors and bispecific antibodies.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While “examples explicitly covering the full scope of the claim language” typically will not be required, a sufficient number of representative species must be included to “demonstrate that the patentee possessed the full scope of the [claimed] invention.” Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed bispecific antibodies or immunoreceptors. Possession may 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, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). 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).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of bispecific antibodies and immunoreceptors as claimed. 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).
Applicant’s Arguments
Applicant requests the rejection be withdrawn. Applicant submits that this rejection has been addressed by the amendment to the claims. To the extent that the rejection has not been addressed, Applicant submits that the specification provides information on all amino acid sequences of {A-Bn], as well as information and sequences on exemplary immunoreceptors that comprise said amino acid sequences and are put into practice. Additionally, it discloses drawings of immunoreceptor designs. Moreover, the “90%” language is justified because this is an extremely well characterized sequence, but functionally and structurally. Further, the application provides examples on the structure of the immunoreceptors, e.g. that they consist of an extracellular antigen-binding domain, a spacer domain, a transmembrane domain, and an intracellular signaling domain. This structure is shared by CARs, TCRs and BCRs, as is well known and also described in the application (see claims and p. 30). Further the application provides functional features, e.g. the immunoreceptors must have a good functionality, such as being able to bind to tumor cells and having a low immunogenicity (e.g. as compared to immunoreceptors comprising repeats of an IgG1 hinge domain and/or an IgG4 hinge domain) and must have a low immunogenicity (see claims, p. 30). Tests to show that the receptors are functional are known and described in the application (e.g. in vivo functional assays in tumor bearing mice to evaluate for tumor reduction and persistence of the immune cells carrying the immunoreceptors claimed (Example 7) or in vitro functional assay to test cytotoxic effects and cytokine secretion of the immune cells carrying the immunoreceptors claimed (Examples 2-6). Likewise, methods to test the immunogenicity are described in the present application such as ELISA-based methods (see p. 35-36). Thus, the application provides a combination of identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus. Applicant submits that this rejection has been adequately addressed.
Response to Arguments
Applicant's arguments filed 10/30/2025 have been fully considered but they are not persuasive. Examiner respectfully disagrees with Applicant’s assertion that the specification provides information on all amino acid sequences of [A-Bn]. First, the claims are not limited to the sequence of [A-Bn], but includes 90% variance of this sequence as well as up to 10 repeats of B (SEQ ID NO: 1). The claims nor the specification define which amino acid residues are being modified; as such, that encompasses potentially thousands of immunoreceptors comprising this IgG3 middle hinge repeat for which Applicant has failed to demonstrate that Applicant was in possession of the genus of immunoreceptors. Furthermore, Applicant's arguments do not comply with 37 CFR 1.111(c) because they do not clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited. Further, they do not show how the amendments avoid such references. Lastly, Applicant has not cited a specific section of the specification that would support Applicant’s assertions that information on all amino acid sequences of [A-Bn] were provided.
Additionally, while Applicant is entitled to use functional language in the description of claimed agents, according to MPEP 2163, an invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. This matches the facts here. The claims require specific functionality for the extracellular antigen-binding domain of the immunoreceptors, but neither the instant disclosure, nor the art, provide description of the corresponding structure for that functionality or a representative number of species for the agents/components. For example, the extracellular antigen-binding domain of the immunoreceptors is defined by its binding specificity and by their ability to bind to a specific protein sequence. In both the base claims and the dependent claims, for at least one agent/component in each claim, the claims only describe what the agent/component does, not what the agents/components are. Even when given possible sequences from which to select a fragment of a peptide that would bind to, the question remains about which one(s) of the encompassed peptides would actually perform the claimed function. While methods to identify the peptides with the required function may be routine in the art, the fact that any experimentation is required to figure out exactly what is encompassed necessarily means that applicant has not sufficiently described the claimed subject matter.
There are thousands of possible immunoreceptors encompassed by the instant claims. One of skill in the art could not immediately envisage the encompassed species in each genus from the guidance provided in the instant specification and claims. Applicant has supplied a few species of immunoreceptors, which binds to a protein that consist of upper hinge (SEQ ID NO: 2), the start of the middle hinge (CPRCP, SEQ ID NO: 59) and 0-10 copies of the EPKSCDTPPPCPRCP motif (SEQ ID NO: 1) that target CD19, ROR1, ROR2, FLT3, or Siglec-5, some of which are not included in the sequences of the instant claims and may comprise at least part of the epitope to which the antibody binds. Further, the claims are not limited to this species, or even polyclonal immunoreceptors. The claims encompass all immunoreceptors that comprise at least 90% sequence identity with the amino acid sequence of [A-Bn] wherein n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. This encompasses an extremely broad genus of peptides with a specific function, for which no correlating structure is provided.
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). Describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene' s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also 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.").
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Further, arguments relating to the functional assays may be more appropriately directed to the invention' s enablement, since the method of testing immunogenicity would detail how to use the invention. However, the enablement of the invention has not been rejected by the Examiner.
As such, the written description rejection is maintained.
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 (i.e., changing from AIA to pre-AIA ) 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, 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.
Claims 52-56, 59, and 67-71 are rejected under 35 U.S.C. 103 as being unpatentable over Shah (WO 2019/079486 A1, publication date: 04/25/2019; previously submitted with the restriction requirement mailed on 03/18/2025), and further in view of Plomp et al (Molecular & Cellular Proteomics 14: 10.1074/mcp.M114.047381, 1373–1384, 2015; previously submitted with the restriction requirement mailed on 03/18/2025).
With respect to instant claims 52-56 and 67-71, Shah discloses of methods and compositions including antigen-binding polypeptides comprising a stalk region and a stalk extension region (see Abstract). The antigen-binding polypeptides can be a CAR (see Abstract) or a bispecific antibody (see [0082]. Shah discloses that the chimeric polypeptide comprises (i) an antigen-binding region, (ii) a transmembrane region, and (iii) a spacer region connecting said transmembrane region with the antigen binding region, wherein the spacer region comprises a stalk region designated as “s” and at least one stalk extension region, designated as “s’-n,” wherein n represents the number of units of s’ in the space region, and wherein n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 (see [0007]). Shah discloses that the chimeric polypeptide can comprise an intracellular signaling domain (see [0008], [0083], and [00109]). Shah discloses that the chimeric polypeptide binds to an epitope on at least one of CD19, BCMA, CD44, a-Folate receptor, CAIX, CD30, ROR1, CEA, EGP-2, EGP-40, HER2, HER3, Folate-binding Protein, GD2, GD3, IL-13R-a2, KDR, EDB-F, mesothelin, CD22, EGFR, GPC3, CSPG4, HER1/HER3, HER2, CD44v6, CD44v7/v8, CD20, CD174, CD138, LI-CAM, FAP, c-MET, PSCA, CSI, CD38, IL-11Ra, EphA2, CLL-1, Folate receptor a, Mucins, MUC-1, MUC-16, MAGE-Al, h5T4, PSMA, TAG-72, EGFR, CD20, EGFRvIII, CD123 VEGF-R2, NY-ESO-1, Titin, MART-I, HPV, HBV, MAGE-A4, MAGEAI0, MAGE A3/A6, gpl00, MAGE-Al, or PRAME (see [0011] and [0016]). Shah discloses that the CAR comprises an antigen binding moiety can be an scFv comprising a variable heavy (VH) and light (VL) domains that are connected with a linker (see [00139]). Shah discloses that the stalk region comprises IgG3 hinge region (see [00115]). Specifically, Shah discloses of SEQ ID NO:41 which is the human IgG3 sequence and shares 100% identity with instant SEQ ID NO: 2 and instant SEQ ID NO: 1 with 3 repeat motifs (see alignments).
SEQ ID NO: 2 Alignment
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SEQ ID NO: 1 Alignment
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698
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With respect to instant claim 59, Shah discloses that the claimed chimeric polypeptides can be administered to patients with cancer (see [00181]-[00186]).
Shah does not disclose that the chimeric polypeptide does not comprise an IgG3 CH2 and/or CH3 domain. This is remedied by Plomp et al.
Plomp et al disclose that IgG3 represents ~8% of the total amount of IgG in human serum and stands out from the other IgG subclasses because of its elongated hinge region and enhanced effector functions (see Abstract). Plomp et al disclose that the hinge region and CH2 domain of IgG3 are instrumental in binding to the high affinity FcγRI receptor (see page 1373, right column).
Therefore, it would have been obvious to combine the teachings of Shah and Plomp et al to develop the claimed invention because Shah disclose that the chimeric polypeptides can be used in methods of treating cancers. Further, the claimed immunoreceptor can be made without the CH3 domain of IgG3 because it has been determined that the hinge region and CH2 domain of IgG3 are significant in the binding affinity of Fcγ receptors (as evidenced by Plomp). Inversely, it would be advantageous to lose binding affinity of Fcγ receptors (i.e., lose the CH2 domain) because it may exhibit anti-inflammatory properties as evidenced by Plomp (see pg. 1374, left column).
Applicant’s Arguments
Applicant requests the 103 rejection be withdrawn (see pages 23-27 of the Remarks filed 10/30/2025).
Applicant reiterates that the Examiner in the rejection stated “Shah does not disclose that the chimeric polypeptide does not comprise an IgG3 CH2 and/or CH3 domain”. To the extent that this rejection has not been addressed by the amendment to claim 52, Applicant submits that the claimed immunoreceptor is inventive over Shah and the other references due to structural non-obviousness, i.e. the chimeric polypeptides of SHAH have different sequences compared to the presently claimed immunoreceptors… The spacer of SHAH comprises a stalk region that can dimerize (through the formation of disulfide bonds), and stalk extension region(s) that are preferably mutated so that they do not dimerize… Consequently, the skilled person would expect each extension to contain the full sequence identified by SEQ ID NO: 41 as a stalk extension region, repeated “n” – times and mutated so that the dimerization sites are reduced. This would result in a completely different spacer structure to the one currently claimed… This is not remedied by Plomp et al. which “disclose that the hinge region and CH2 domain of IgG3 are instrumental in binding to the high affinity FcyRI receptor”. According to the Examiner, the skilled person would consider it “advantageous to lose binding affinity of Fcy receptors (i.e., lose the CH2 domain) because it may exhibit anti-inflammatory properties as evidenced by Plomp”. However, and as mentioned by the Examiner, Plomp et al. discloses that both the hinge region and the CH2 domain are involved in binding the FcyRI receptor. In addition, Plomp et al. does not mention any disadvantages to maintaining the CH3 region. Thus, considering Plomp et al. the skilled person would not consider creating an immunoreceptor comprising one or more IgG3 middle hinge repeat domain motifs, wherein the immunoreceptor does not comprise an IgG3 CH2 and/or CH3 domain. Hence, the skilled person would never arrive at the presently claimed subject matter. Thus, even when combining the teachings of SHAH with Plomp et al., i.e. by removing a CH2 region of the polypeptide disclosed in SHAH, the skilled person would still arrive at a completely different CAR construct design.
Response to Arguments
Applicant's arguments filed 10/30/2025 have been fully considered but they are not persuasive.
First, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As stated in the rejection, Shah discloses of methods and compositions including antigen-binding polypeptides comprising a stalk region and a stalk extension region (see Abstract). The antigen-binding polypeptides can be a CAR (see Abstract) or a bispecific antibody (see [0082]. Shah discloses that the chimeric polypeptide comprises (i) an antigen-binding region, (ii) a transmembrane region, and (iii) a spacer region connecting said transmembrane region with the antigen binding region, wherein the spacer region comprises a stalk region designated as “s” and at least one stalk extension region, designated as “s’-n,” wherein n represents the number of units of s’ in the space region, and wherein n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 (see [0007]). Shah discloses that the chimeric polypeptide can comprise an intracellular signaling domain (see [0008], [0083], and [00109]). Shah discloses that the chimeric polypeptide binds to an epitope on at least one of CD19, BCMA, ROR1, CD20, and other antigens (see [0011] and [0016]). Shah discloses that the CAR comprises an antigen binding moiety can be an scFv comprising a variable heavy (VH) and light (VL) domains that are connected with a linker (see [00139]). Shah discloses that the stalk region comprises IgG3 hinge region (see [00115]). Specifically, Shah discloses of SEQ ID NO:41 which is the human IgG3 sequence and shares 100% identity with instant SEQ ID NO: 2 and instant SEQ ID NO: 1 with 3 repeat motifs (see alignments above). Further, while SHAH may not disclose that the chimeric polypeptide does not comprise an IgG3 CH2 and/or CH3 domain, Plomp et al disclose that IgG3 represents ~8% of the total amount of IgG in human serum and stands out from the other IgG subclasses because of its elongated hinge region and enhanced effector functions (see Abstract). Plomp et al disclose that the hinge region and CH2 domain of IgG3 are instrumental in binding to the high affinity FcγRI receptor (see page 1373, right column). As such, it would have been obvious to combine the teachings of Shah and Plomp et al to develop the claimed invention because Shah discloses that the chimeric polypeptides comprising an IgG3 middle hinge domain motif and can be made without the CH3 domain of IgG3 because it has been determined that the hinge region and CH2 domain of IgG3 are significant in the binding affinity of Fcγ receptors (as evidenced by Plomp). Inversely, it would be advantageous to lose binding affinity of Fcγ receptors (i.e., lose the CH2 domain) because it may exhibit anti-inflammatory properties as evidenced by Plomp (see pg. 1374, left column).
Applicant is reminded that the present claims are drawn to immunoreceptors comprising one or more IgG3 middle hinge repeat domain motifs. The transitional phrase “comprising” is interpreted as an open-ended transitional term and does not exclude additional, unrecited elements or method steps (see according to MPEP 2111.03(I)); meaning that the stalk region of SHAH is not excluded from the present invention. Additionally, the present claims indicate that the [A-Bn] sequence can be without the Bn sequence (i.e., SEQ ID NO: 1) because the present claims state that n can be 0. Therefore, the non-dimerized stalk extension region of SHAH is still encompassed within the present claims. Lastly, as stated above, SEQ ID NO: 41 of SHAH shares 100% identity with instant SEQ ID NO: 2 and instant SEQ ID NO: 1 with 3 repeat motifs. As stated in Applicant’s response, SHAH also states that the stalk region can comprise IgG3 hinge region or a sequence with at least 80% homology to the IgG3 hinge region (SEQ ID NO: 41); thus, one would not expect that the stalk will contain the full sequence identified by SEQ ID NO: 41 as Applicant has argued.
With respect to Applicant’s argument that SHAH contains no teaching that the modulation of IgG3 spacers could help to minimize immunogenicity, it is noted that the features upon which applicant relies (i.e., modulating IgG3 spacers to minimize immunogenicity) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Further, Plomp et al disclose that the hinge region and CH2 domain of IgG3 are instrumental in binding to the high affinity FcγRI receptor (see page 1373, right column), meanwhile the length of the hinge region can also display a high degree of variation (see page 1374, left column).
As such, the 103 rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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18/019,238
Claims 52-56, 59, and 70-71 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 81-82, 89-91, and 95-101 of copending Application No. 18/019,238 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘238 application is drawn to a siglec-6-binding polypeptide that comprises or consists of a chimeric antigen receptor (CAR), the siglec-6-binding polypeptide comprising or consisting of a siglec-6-binding CAR, wherein the CAR comprises at least one extracellular ligand binding domain, a transmembrane domain and at least one intracellular signaling domain, wherein: (i) said extracellular ligand binding domain comprises a siglec-6-binding element represented by an amino acid sequence shown in SEQ ID NO: 25 or by an amino acid sequence having at least 90% identity to an amino acid sequence shown in SEQ ID NO: 25; and/or (ii) the polypeptide comprises an amino acid sequence shown in any one of SEQ ID NOs: 27, 29, 31 or 33 or an amino acid sequence having at least 90% identity to an amino acid sequence shown in any one of SEQ ID Nos: 27, 29, 31 or 33 (see claim 81). SEQ ID NO: 33 shares 100% identity to instant SEQ ID NO: 167 (which consequently, comprises instant SEQ ID Nos: 1 and 2).
The ‘238 application is also drawn to the siglec-6-binding polypeptide according to claim 81, wherein: (a) the extracellular ligand binding domain comprises a spacer domain, such as spacer domain from CD8α, IgG3 or IgG4;(b) said transmembrane domain comprises a CD28 transmembrane domain, preferably represented by an amino acid sequence shown in SEQ ID NO: 13 or by an amino acid sequence having at least 90% identity to an amino acid sequence shown in SEQ ID NO: 13:(c) said intracellular signaling domain comprises a costimulatory domain and a CD3 zeta domain, wherein the CD3 zeta domain is preferably represented by an amino acid sequence shown in SEQ ID NO: 19 or by an amino acid sequence having at least 90% identity to an amino acid sequence shown in SEQ ID NO: 19, and wherein the costimulatory domain is preferably: a CD28 cytoplasmic domain, wherein the CD28 cytoplasmic domain is preferably represented by an amino acid sequence shown in SEQ ID NO: 15 or by an amino acid sequence having at least 90% identity to an amino acid sequence shown in SEQ ID NO: 15, or a 4-1BB costimulatory domain, wherein the 4-1BB costimulatory domain is preferably represented by an amino acid sequence shown in SEQ ID NO: 17 or by an amino acid sequence having at least 90% identity to an amino acid sequence shown in SEQ ID NO: 17 (see claim 82). SEQ ID Nos: 13, 19, and 17 share 100% identity with instant SEQ ID NO: 110.
Lastly, the ‘238 application is drawn to a method of treatment comprising administering an immune cell according to claim 89 or a pharmaceutical composition comprising the same to a subject (see claims 97-101. As such, the ‘238 application anticipates the present invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Arguments
Applicant submits that this rejection has been addressed by the amendment to the claims. To the extent that it has not been addressed, the rejection is requested to be held in abeyance until patentable subject matter is identified (see page 27 of the Remarks filed on 10/30/2025).
Response to Arguments
Applicant's arguments filed 10/30/2025 have been fully considered but they are not persuasive.
Applicant is reminded that a request for a rejection to be held in abeyance does not “distinctly and specifically points out the supposed errors in the examiner’s action” as required under 37 CFR 1.111. See MPEP 714.02.
Further, Applicant is advised that a rejection under double patenting precludes the identification of allowable subject matter. Applicant has not filed a terminal disclaimer, and the claims remain rejected for reasons set forth above.
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As such, the double patenting rejection is maintained.
New Objections and Rejections Necessitated by Amendment
Claim Objections
Claims 52, 56, and 67 are objected to because of the following informalities:
Claims 52 and 67 are missing a conjunction between “9,” and “10”.
Claim 56 does not end with a period. Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 69 and 70 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 69 recites “wherein the linker comprised in the extracellular antigen-binding domain comprises the one”. It is unclear what “the one” is referring to with respect to the extracellular antigen-binding domain. If Applicant is referring to the “one or more IgG3 middle hinge domain repeat motifs”, the examiner suggests amending the claim to recite “the one or more IgG3 middle hinge domain repeat motifs”.
Claim 70 is drawn to the immunoreceptor according to claim 55, wherein the scFv comprises, as heavy/light chain variable sequences comprised in the first/second domain, heavy/light chain variable sequences of scFvs specific for one of the following antigens. The claim is indefinite because the claim requires heavy chain or light chain variable sequences without actually setting forth the sequences. As such, one would not be apprised to the scope of the claim because the claim only recites the scFvs function without the correlating structure.
Claim Rejections - 35 USC § 112(a) Enablement
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.
Claim 59 is 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.
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.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement
requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S.
261, 270 (1916) which postured the question: is the experimentation needed to practice the
invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858
F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does
not use the term "undue experimentation," it has been interpreted to require that the claimed
invention be enabled so that any person skilled in the art can make and use the invention without
undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence
to support a determination that a disclosure does not satisfy the enablement requirement and whether
any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content
of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors most relevant for this rejection are: (A) the breadth of the claims; (B) the nature of the invention; (E) the level of predictability in the art; (F) the amount of direction provided by the inventor; (G) the existence of working examples; and (H) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In regard to Wands factors (A) and (B), the breadth of the claims needed to enable the invention
is determined by whether the scope of enablement provided to one skilled in the art by the disclosure is
commensurate with the scope of protection sought in the claims. AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003); In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). The propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one
skilled in the art could make and use the entire scope of the claimed invention without undue
experimentation.
The nature of the invention is a method of treating a cancer, an autoimmune disease, an infectious disease or a degenerative disease comprising administering the immunoreceptor according to claim 52 to a patient. Therefore, the nature of the invention is a biochemical case, where there is natural unpredictability in performance of certain species other than those specifically enumerated; see MPEP § 2163. Accordingly, it is the Office’s position that undue experimentation would be required to practice the functionality of the claimed method, with a reasonable expectation of success, because it would not be predictable from the disclosure of any one particular species may or may not work; see MPEP § 2164.03.
In regard to Wands factors (C), (D), and (E), the state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains and provides evidence for the degree of predictability in the art; see MPEP § 2164.05(a). The claims encompass treating cancer, an autoimmune disease, an infectious disease or a degenerative disease with a large genus of immunoreceptors. These cancers are highly heterogeneous at both the molecular and clinical level. Additionally, it is known in the art that cancer cells arising from different tissues differ in etiology and response to treatment. Heppner et al. (Cancer Metastasis Review 2:5-23; 1983) discuss the heterogeneity of tumors from different tissues, as well as the same tissue. A key point made by Heppner et al. is that tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult.
Additionally, Bally et al. (US Patent No. 5,595,756A, publication date: 01/21/1997) stated, "Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment limiting toxicities (See column 1).
Sporn et al. (Chemoprevention of Cancer, Carcinogenesis, Vol. 21 (2000), 525-530) teaches the magnitude of mortality of cancers and that mortalities are in fact still rising and that new approaches to a variety of different cancer are critically needed. Sporn et al. also teach that “given the genotype and phenotype heterogeneity of advanced malignant lesions as they occur in individual patients, one wonders just exactly what are the specific molecular and cellular targets for the putative cure.”
Furthermore, the art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al. (Cancer and Metastasis Reviews, 2000, 19: 167-172) indicate that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to permit screening of hybridoma supernatants…In vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality (see p. 167, left column, 1st paragraph).
Gura T (Science, 1997, 278(5340): 1041-1042, encloses 1-5) indicates that “the fundamental problem in drug discovery for cancer is that the model systems are not predictive at all” (see p. 1, 2nd paragraph). Furthermore, Gura indicates that the results of xenograft screening turned out to be not much better than those obtained with the original models, mainly because the xenograft rumors don’t behave like naturally occurring tumors in humans—they don’t spread to other tissues, for example (see p. 2, 4th paragraph). Further, when patient’s tumor cells in Petri dishes or culture flasks and monitor the cells’ responses to various anticancer treatments, they don’t work because the cells simply fail to divide in culture, and the results cannot tell a researcher how anticancer drugs will act in the body (see p. 3, 7th paragraph).
Furthermore, Jain RK (Scientific American, July 1994,58-65) indicates that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain (see p. 58, left most column, 1st paragraph). Further, Jain indicates that to eradicate tumors, the therapeutic agents must then disperse throughout the growths in concentrations high enough to eliminate every deadly cell…solid cancers frequently impose formidable barriers to such dispersion (see p. 58, bottom of the left most column continuing onto the top of the middle column). Jain indicates that there are 3 critical tasks that drugs must do to attack malignant cells in a tumor: 1) it has to make its way into a microscopic blood vessel lying near malignant cells in the tumor, 2) exit from the vessel into the surrounding matrix, and 3) migrate through the matrix to the cells. Unfortunately, tumors often develop in ways that hinder each of these steps (see p. 58, bottom of right most column). Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Hait (Nature Reviews/Drug Discovery, 2010, 9, pages 253-254) states that “The past three decades have seen spectacular advances in our understanding of the molecular and cellular biology of cancer. However, with a few notable exceptions, such as the treatment of chronic myeloid leukemia with imatinib, these advances have so far not been translated into major increases in long-term survival for many cancers. Furthermore, data suggest that the overall success rate for oncology products in clinical development is -10%, and the cost of bringing a new drug to market is over US$1 billion.” (see page 253, left column, the 1st paragraph). Hait further teaches “The anticancer drug discovery process often begins with a promising target; however, there are several reasons why the eventual outcome for a particular cancer target may be disappointing. For example, the role of the target in the pathogenesis of specific human malignancies may be incompletely understood, leading to disappointing results”, “First, many targets lie within signal transduction pathways that are altered in cancer, but, owing to the complex nature of these pathways, upstream or downstream components may make modulating the target of little or no value”; “Second, target overexpression is often overrated. There are some instances in which overexpression predicts response to treatment.”; and “Another confounding factor is that cancer is more than a disease of cancer cells, as alterations in somatic or germline genomes, or both, create susceptibilities to transformational changes in cells and in the microenvironment that ultimately cooperate to form a malignant tissue. The putative role of cancer stem cells in limiting the efficacy of cancer therapeutics is also an area of intense interest. Therefore, effective treatments may require understanding and disrupting the dependencies among the multiple cellular components of malignant tissues. Single nucleotide polymorphisms in genes responsible for drug metabolism can further complicate the picture by affecting drug pharmacokinetics; for example, as with the topoisomerase inhibitor irinotecan.”, for example, page 253, Section “Understanding the target in context”. Hait also teaches “Drug effects in preclinical cancer models often do not predict clinical results, as traditional subcutaneous xenografting of human cancer cell lines onto immunocompromised mice produces ‘tumors’ that fail to recapitulate key aspects of human malignancies such as invasion and metastasis. Several improvements have been made, including orthotopic implantation and use of mice with humanized hematopoietic and immune systems. Newer genetic mouse models can also allow analyses of tumor progression from in situ through locally advanced and, in certain cases, widespread metastatic disease. However, whether or not these models will more accurately predict drug activity against human cancer remains to be determined. Other alternatives, including three-dimensional tissue culture or xenografts of fresh human biopsy specimens onto immunocompromised mice, have the potential advantage of including the human microenvironment. However, these approaches have yet to prove their value relative to their cost.”, for example, page 253, Section “Predictive models”. Furthermore, Hait teaches that “It is now widely thought that biomarkers will drive a personalized approach to cancer drug development. The aim is that they will cut costs, decrease time to approval, and limit the number of patients who are exposed to potential toxicities without a reasonable chance of benefit — as exemplified by the development of imatinib and trastuzumab. However, recent attempts at repeating these successes in other cancer types have been less successful.”, for example, page 254, Section “Stratified/personalized medicine”.
The challenges facing cancer drug development are further confirmed and discussed in Gravanis et al. (Chin Clin Oncol, 2014, 3, pages 1 -5). Gravanis et al. teach “The generic mechanism of action for cytotoxics made the prediction of which tumor types might respond to them very difficult, if not impossible, and necessitated a ‘trial and error’ approach against many different types of tumors.” and “The most prominent change in oncology drug development in the last 20 years has been the shift from classic cytotoxics to drugs that affect signaling pathways implicated in cancer, which belong to the so called ‘targeted therapies’.”, for example, page 1, Section “From cytotoxics to targeted therapies: how far are we from truly personalized medicine?”. Gravanis et al. further teach “Although constantly progressing, an understanding of cancer biology is far from complete. The ability to develop new compounds or generate biological data predictive of the clinical situation relies on good quality basic research data, although the complexity and constantly evolving biology of the tumor may be to blame for the frequent non-reproducibility of research results. Systemic biology approaches of the -omic type still generate largely incomprehensible, mostly due to their volume, analytical data, few pieces of which are currently actionable/drug-g-able. Finally, animal models of cancer are similarly unable to predict the clinical situation (for example, page 3, right column, the 2nd paragraph).
Beans (PNAS 2018; 115(50): 12539-12543) teaches that across cancer types, 90% of cancer deaths are caused not by the primary tumor but by metastasis. Beans teaches that although some drugs may shrink metastases along with primary tumors, no existing drugs treat or prevent metastasis directly (See page 12540). Beans states “Without a targeted approach, metastatic tumors often reemerge. “We shrink them, we send them back to their residual state, and they reenact those survival functions and retention of regenerative powers that made them metastasis-initiating cells in the first place” (See page 12540). Beans teaches that one of the major scientific challenges of studying metastatic disease is that different forms of cancer seem to metastasize through different mechanisms and the same form of cancer may metastasize differently in different subsets of patients (See page 12542). Of note, Beans states “It’s unlikely that one researcher is going to find one pathway that proves to be the key to metastasis” (See page 12542). Beans also teaches that translating many findings into therapies also presents unique hurdles in that it is difficult to measure the effectiveness of the therapy. Secondary tumors are often minuscule, and therefore, measuring success by tumor shrinkage may not work. Measuring the incidence of metastasis after treatment is also more difficult (See page 12542).
Given Bally et al. teaching of treatment-limiting toxicities in clinical use; Sporn's teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype; Auerbach et al. teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response; Gura's teaching that the models are unpredictable; Jain's teaching that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain; both Hait and Gravanis et al teaching various challenges facing cancer drug development, such as an understanding of cancer biology is far from complete, drug effects in preclinical cancer models often do not predict clinical results and many others; and Beans teachings that the field is highly underdeveloped with regards to preventing and treating cancer metastasis; the cited references demonstrate that the treatment of cancer is highly unpredictable, if even possible for many cancers. In conclusion, the art provides evidence that heterogeneity in cancers can display unpredictability in response to the same treatment.
With respect to the autoimmune diseases, an autoimmune disease is a condition arising from an abnormal immune response to a normal body part. Nearly any body part can be involved. Common symptoms include low grade fever and feeling tired. The cause is generally unknown. Examples include diabetes mellitus type 1, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, scleroderma, vitiligo, and systemic lupus erythematosus.
Blumberg et al. (Nat Med. (2012); 18(1): 35–41) teach that one of the greatest problems in translating therapies into clinical practice in autoimmunity are the numerous failures that have been the results of clinical trials. Despite the rapid progress that has been made in understanding the immune system, most of the underlying data has come from animal models, which necessarily only partially represent what is observed in humans. To compound this limitation, there exists no standardized definition of the normal human immune system, no comprehensive understanding of how this normal system is altered in autoimmune diseases and no understanding of the relationship between these immunophenotypic characteristics and either the genetic composition of the host or the environmental stimuli that either promote or protect from the development of autoimmunity (see pages 1-3). It is important to remember that the claims are even broader than the field of autoimmune disorders, including diseases such as, for example, infectious diseases, neurodegenerative disease, ischemia/reperfusion injury and transplantation rejection which are beyond the scope of autoimmune disorders.
As such, the art indicates autoimmune diseases can affect the efficacy of therapeutics used to treat it. Therefore, the art is unpredictable regarding treatment of all autoimmune diseases with a single compound or class of compounds.
In regard to Wands factors (F), (G) and (H), the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech
Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004).
The claim is drawn to a method of treating a cancer, an autoimmune disease, an infectious disease or a degenerative disease comprising administering the immunoreceptor according to claim 52 to a patient.
The working examples provided by Applicant do not demonstrate a method of reducing all cancers, autoimmune diseases, infectious diseases, or degenerative diseases to a patient with the large genera of immunoreceptors. Examples 2-6 demonstrate experiments testing five IgG3 hinge variants (IgG3_MiH1, IgG3_MiH2, IgG3_MiH3, IgG3_MiH4 and IgG3_MiH5) and comparing them to an IgG4 construct. Example 2 indicates that all variants showed a comparably strong specific proliferation upon encounter of CD19-expressing target cells; variants IgG3_MiH1 and IgG3_MiH2 displayed a pronounced cytotoxic effect similar to that of the IgG4 CAR while cytolysis was reduced for longer IgG3 variants. Example 3 indicates that the IgG3_MiH1 variant comprising the 4-2 scFv and IgG4 showed comparable proliferation, cytotoxicity and cytokine secretion upon antigen encounter, whereas IgG3_MiH1 comprising the R11 scFv did not induce antigen-specific proliferation or cytotoxic response upon encounter of ROR1+ target cells while all other variants led to effective tumor cell lysis with IgG3_MiH2, IgG3_MiH3, and IgG3_MiH4 being as effective as the IgG4 variant. The inability of IgG3_MiH1 to induce antigen-dependent T cell effector functions is caused by a spacer length insufficient to reach the epitope (see pg. 133). Example 4 demonstrates that the shortest IgG3 variant (IgG3_MiH1) showed the best proliferation upon antigen encounter, thereby surpassing the IgG4 variant by a wide margin, while longer IgG3 variants proliferated much less (see Figure 5A). Variants IgG3_MiH2 and IgG3_MiH3 led (together with the IgG4 variant) to best cytotoxic effects, while IgG3_MiH1, IgG3_MiH4, and IgG3_MiH5 exhibited far less cytotoxicity (see Figure 5B). IgG3_MiH1 and IgG3_MiH2 showed comparable amounts of IFNγ to be released while the longer IgG3 variants secreted less (see Figure 5C). Example 5 demonstrates that the shortest spacer variant investigated (IgG3_MiH1) showed the highest level of antigen-specific proliferation, outperforming the IgG4 variant equipped with a long IgG4-based spacer (hinge-CH2-CH3). Even though none of the IgG3 variants could reach the level of IgG4 for killing of the SLAMF7 expressing myeloma cell line MM.1S, IgG3 variants equipped with 1, 2, or 3 IgG3_MiH repeats led to profound cytolysis; however, the IgG3_MiH1 IgG3 variant led to the highest secretion with IgG3_MiH2 equaling the IgG4 variant right behind (see Figure 6). Example 6 demonstrates that IgG3_MiH1 outperforms the IgG4 variant (IgG4 long) in specific proliferation and cytokine secretion (IFNγ) encounter of the antigen, while both variants display equal cytotoxic capacity.
In an in vivo experiment, the IgG3_MiH1 variant and the IgG4 CAR led to complete eradication of the CD19+ Raji tumor cells; though tumor cells eventually grew out in all mice, the IgG3_MiH1 variant delayed this outgrow and led to significantly prolonged survival rate as compared to the IgG4 variant (see Figure 8A-B). Another mouse experiment was performed applying ROR1-specfiic CAR T cells equipped with the R11 scFv in mice engrafted with Jeko-1 for 7d; while neither the IgG4 spacer variant, nor IgG3 variants IgG3_MiH1 and IgG3_MiH4 influenced Jeko-1 tumor growth and survival of the treated animals, IgG3_MiH3 and especially IgG3_MiH2 led to attenuated tumor growth and prolonged animal survival (see Figure 9).
Lastly, Example 18 demonstrates in vitro cytotoxic function of additional advanced IgG3 format CAR T cells and comparison to CD8α format. In this example, the cytotoxic capacity of T cells equipped with optimized IgG3 variants of additional CARs targeting ROR1 (4-2 scFv), FLT3 (4G8 and BV10) and Siglec-6 (JML-1 scFv, comprising SEQ ID Nos: 49 and 50), and compared them to CARs with the same scFvs constructed in the widely applied CD8α setup (CD8α hinge and transmembrane domains). All advanced IgG3 versions exhibited a significantly enhanced cytotoxic potential as compared to CD8α versions (see Figure 22A-D).
Because the specification only studied a few immunoreceptors with a few cancers, one cannot assume that the method of treating a cancer, an autoimmune disease, an infectious disease or a degenerative disease with any immunoreceptor will work similarly to the examples provided in the specification. In the absence of empirical determination, one skilled in the art would be subjected to undue experimentation to determine if the claimed method of treating a cancer, an autoimmune disease, an infectious disease or a degenerative disease in a patient would result in therapeutic response as recited in the claims.
Applicant is reminded that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”. See Genentech, 108 F.3d 1361, 1366 (Fed. Cir. 1997).
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674