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 .
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.
DETAILED ACTION
This action is in response to claim amendments filed 5/4/26. Claims 1, 4, 7, 12-17, and 21-31 are pending and under examination.
Claim Rejections - 35 USC § 112
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 22 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 22 is a composition claim (a mammalian cell) but contains an active step (“is electroporated”). This is not a clear product-by-process limitation and does not alter the structure of the resulting cell compared to such a cell comprising the mRNA that was not electroporated. This supports the conclusion that this is an active method step. Adding process steps to a product claim is indefinite as it creates confusion as to when direct infringement occurs; MPEP §2173.05(p)(II).
Therefore, claim 22 is indefinite.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, 7, 12-17, and 21-31 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is directed to a cell comprising mRNA encoding a multispecific scFv that binds BCMA and CD3. In order to envisage an mRNA that encodes the protein, one must be able to envisage the protein. Claim 1 requires this protein to be 95% identical to SEQ ID NO: 140 and defines the CD3 binding domain solely by function. Claim 7 is directed to the protein encoded by claim 1. A BCMA binding region defined by a partial structure (95%) and a CD3 binding domain defined by no structure does not meet the written description requirement.
Antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. The hyper variable regions (HVRs), i.e., complementarity determining regions (CDRs) of an antibody, are well established in the art as the portion of the binding region which imparts the specificity of an antibody. However, there is no way to a priori look at an antigen sequence (BCMA or CD3) and envisage the combination of six CDRs that will bind that antigen. First, even highly related CDRs may not bind the same target. See for example Kussie (cited on form 892) who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-axophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (e.g., abstract). Second, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (p.7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on page 11).
Thus, the art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. As a further example, see Chen (cited on form 892) which demonstrates single amino acid changes in the VH CDR2 sequence can increase binding, decrease binding, destroy binding, or have no effect on binding when compared to the wild-type antibody.
Making changes to the CDR sequence of an antibody is a highly unpredictable process and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions.
The specification discloses SEQ ID NO: 140 for BCMA binding protein and SEQ ID NO: 33 for CD3 binding protein. The specification does not describe specific residues in these sequences which tolerate mutation nor a representative number of variations to suggest possession of the antibodies as broadly as claimed. As discussed above, without any way to determine how broad the genus of such antibodies is, there is no way to determine if these antibodies represent the full breadth of what is claimed. The disclosure of these specific antibodies would not convey to the artisan that Applicant was in possession of the full genus of all antibodies which possess the required functions nor does it allow the skilled artisan to envisage the specific structure of such antibodies.
Further note the decision in Amgen v. Sanofi 2017, where the Court supported previous decisions (Centocor 2011; Abbvie 2014) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”. MPEP 2163 states “disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional”. With 95% sequence identity to SEQ ID: 140 up to 12 amino acids may be altered. This would allow an entire CDR to be replaced by an arbitrary sequence. Even in claims such as claim 28 that allows for only 3 amino acid substitutions, these could be in the CDR sequences and the art of record establishes that even a single CDR mutation is unpredictable. Arbitrarily altering any amino acid in the CDR of an antibody is unpredictable and the specification does not convey possession of any CDRs other than those of the disclosed antibodies.
The specification also discloses other BCMA and CD3 antibodies, e.g., those listed in example 4. These additional species do not address any of the deficiencies above. There is no disclosed alignment and no guidance as to how these CDRs inform the artisan regarding acceptable mutations. Additionally, most of these species are listed as “similar” (without explaining this term), which suggests that these are related antibodies and does not describe the breadth of what is claimed.
Considering the disclosure and art as a whole, the skilled artisan could not envisage the breadth of variations within the 95% identity, the 3 mutations, or the binding antibody claimed by function alone.
Therefore, claims 1, 4, 7, 12-17, and 21-31 do not meet the written description requirement.
Claims 15-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating cancers such as myeloma and for treating autoimmune diseases, does not reasonably provide enablement for treating all disease or preventing any disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: 1) nature of the invention, 2) breadth of claims, 3) amount of direction or guidance by the inventor, 4) relative skill of those in the art, 5) level of predictability in the art, 6) state of the prior art, 7) existence of working examples, and 8) quantity of the experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The nature of the invention is treatment and prevention of disease. The breadth is that administering a multispecific BCMA/CD3 scFv antibody in a mammalian cell will treat and prevent all known diseases (claim 15). The guidance in the specification is that these cells function to bind CD3 expressing cells and engage T-cells to produce a cell-mediated immune response to “kill the unwanted BCMA+ cell” (paragraph 65).
The specification does not suggest that all known diseases have BCMA+ cells as their etiologic agent. Rather, most diseases do not. There is no disclosure in the specification or the art that BCMA+ cells are responsible for, e.g., Alzheimer’s disease, influenza infection, muscular dystrophy, etc. Without any reason to expect destruction of BCMA+ cells to treat a certain disease, it would be undue experimentation for others to test the claimed cells across all diseases to determine if and how these cells would treat those diseases.
Treating myeloma (claim 17) and autoimmune diseases (claim 16) is enabled as the instant specification discloses the mechanism which supports a reasonable expectation that this treatment will be therapeutic. However, the instant specification does not provide any working examples of preventing these diseases. In contrast, the art recognizes that these diseases cannot be prevented. Cri (form 892) states “there is currently no known way to prevent multiple myeloma”; note that multiple myeloma is the most common species of myeloma. The specification does not provide any objective evidence which would suggest the instantly claimed cells could prevent diseases previously known to be unpreventable. Shifting the burden of overcoming this technical hurdle to others without sufficient guidance is undue experimentation.
Therefore, claims 15-17 are not enabled for their full scope.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 14 depends from claim 1 and so must require all the limitations of claim 1. However, claim 14 sets forth alternatives such as a composition comprising the mRNA or a vector, which does not require a mammalian cell. Claim 14 does not require all the limitations of claim 1, which violates the requirements of a dependent claim.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Allowable Subject Matter
Regarding the written description rejection, the Examiner notes that a claim reciting a partial sequence identity (such as “95%) would be acceptable so long as the specific CDR sequences are required (the residues explicitly recited by the claim) and not subject to substitution.
There is no prior art rejection of record. For the reasons set forth in the written description rejection, CDRs are unpredictable. There is no prior art of record which discloses the instant BCMA sequence. Close art includes US20200291087 (form 892), which discloses SEQ ID NO: 20 and which is 98.8% identical to instant SEQ ID NO: 140. However, this was assigned to the same assignee (exception under §102(b)(2)) and published by the same inventive entity within 12 months of the instant priority date (exception under §102(b)(1)) and so does not qualify as prior art.
US 12404315 claims binding proteins that binds CD33 or BCMA in the alternative (claim 9). The application does not claim any specific sequence for these binding proteins.
19/084311 claims binding proteins that binds CD33 or BCMA in the alternative. The application does not claim any specific sequence for these binding proteins.
US10934337 claims a BCMA binding protein by CDR sequences. While this patent discloses SEQ ID NO: 20—which is 98.8% identical to instant SEQ ID NO: 140—the CDRs have been modified. For example, instant SEQ ID NO 140 does not contain any of reference SEQ IDs 1-3 at the H-CDR1 position.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ADAM M WEIDNER whose telephone number is (571)272-3045. The examiner can normally be reached M-T 9-18; W-R 9-15.
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/Adam Weidner/Primary Examiner, Art Unit 1675
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