DETAILED ACTION
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
Claims 1-2, 4-6, 8-9, 13, 16-18, 26-27, 29-31, 41-43, 46-47, 49, 70-71, 100-102, and 104-106 are pending and under examination.
Specification
The disclosure is objected to because of the following informalities: Table 4 on Pg. 61 of the specification is not legible.
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.
Claim 5 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 5 recites the limitation “the heavy chain variable region” and “light chain variable region” in lines 1 and 3, respectively. There is insufficient antecedent basis for this limitation in the claim. While the terms appear to refer back to the antibody or antigen-binding fragment of claim 1, not all antibodies or antigen-binding fragments comprise heavy chain and light chain variable regions.
Claim Rejections - 35 USC § 112(a)
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 5 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 written description requirement. The claim 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention
The claimed invention is directed to a method of treating or reducing a risk of transplant rejection comprising administering and anti-CD40 antibody.
Claim 5 teaches the heavy chain variable region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 8.
As part of the claimed method, the anti-CD40 antibody of claim 5 is required to have at least two functions: (1) specifically bind CD40 and (2) treat or reduce the risk of transplant rejection or increase the duration of time before transplant rejection.
The examples in the specification use the anti-CD40 antibody KPL-404, which comprises the heavy chain variable region set forth in SEQ ID NO:7 and the light chain variable region set forth in SEQ ID NO:8. The specification does not disclose alternative antibodies with 85% identity in the heavy and light chain variable regions for use in the method of the claims.
State of the relevant art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
The prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, the unpredictability of single amino acid changes in an antibody is underscored by Winkler (J Immunol. 2000 Oct 15;165(8):4505-14) who teaches that a single amino acid change in a CDR can result in unpredictable and substantial changes in antibody specificity; see entire document (e.g., the abstract).
Similarly, Herold et al. (Sci Rep. 2017 Sep 25;7(1):12276) performed single- and double-point mutations in exemplary antibodies and found that a single point mutation in the VH CDR region can completely abolish antigen binding (Page 8, Paragraph 1, Line 11).
The art thus underscores the importance of fully defined CDRs and evidence from the inventors that they were in possession of each claimed antibody embodiment.
Claim Analysis
In light of the state of the relevant art and the lack of guidance provided in the specification, the claim has the following written description issues:
Claim 5 allows for mutations in the CDRs of the variable regions set forth in SEQ ID NO:7 and SEQ ID NO:8. Thus the 6 CDRs that dictate binding specificity are not sufficiently defined. Neither the claims nor the specification define the minimal structure required in order for the antibody or antigen binding fragment to perform their claimed functions as part of a method for treating or reducing risk of transplant rejection.
One of skill in the art would neither expect nor predict the appropriate functioning of the anti-CD40 antibody or antigen binding fragment as broadly as is claimed. As the disclosure does not define the minimum structure of each component that would impart functionality to each of these claimed elements, the disclosure does not allow those of skill in the art to recognize other members of the claimed genus.
Therefore, the skilled artisan would not reasonably conclude that the inventors, at the time the application was filed, had full possession of structures as broadly claimed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 4, 8-9, 13, 16-18, 26-27, 29-31, 41-43, 46-47, and 49 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mohiuddin (Nat Commun. 2016 Apr 5;7:11138, IDS 06/02/2023) as evidenced by Yu (2018/0078640A1, published 05/22/2018, IDS 06/02/2023) and Nair (J Basic Clin Pharm. 2016 Mar;7(2):27-31).
The disclosure of Mohiuddin is directed to a method of preventing xenograft rejection and describes a reproducible method for the long-term survival of cardiac xenografts from genetically modified pigs transplanted into baboons. Mohiuddin teaches a specific immunomodulatory drug regimen that significantly prolonged survival benchmarks (see Abstract).
Regarding claim 1, pertaining to a method of treating or reducing a risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a human subject receiving or having received a transplant comprising administering an anti-CD40 antibody or antigen-binding fragment thereof from about 10 hours to about 24 hours prior to the transplant and administering the anti-CD40 antibody or antigen-binding fragment thereof within about 1 hour to about 24 hours following the transplant and once the subject achieves hemostasis, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously, Mohiuddin Table 1 outlines the immunosuppressive regimen of the disclosure and teaches: intravenous infusion of an anti-CD40 antibody at: (1) -1 day of the transplant, (2) day 0 post-transplant, and (3) day 1 post-transplant (Pg. 2). Based on the preclinical non-human primate study, Mohiuddin concludes that the regimen appears potentially safe for human patients suffering from end-stage organ failure who might be candidates for initial trials of xenotransplantation (Pg. 5, Left column, Lines 11-16).
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Regarding claim 2, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDRH1, CDRH2, and CDRH3 as set forth SEQ ID NOs: 1-3, respectively, and a light chain variable region comprising a CDRL1, CDRL2, and CDRL3 as set forth in SEQ ID NOs: 4-6, respectively, Mohiuddin teaches the use of the primatized chimeric anti-CD40 antibody clone 2C10R4 (Pg. 8, Left column, Immunosuppression). As evidenced by Yu, the parent antibody of the primatized clone comprises the heavy chain CDRs set forth in instant SEQ ID NOs: 1-3 and light chain CDRs set forth in SEQ ID NOs: 4-6 as shown below:
Regarding claims 16-18, wherein the method of claim 1 further comprises administering a first therapeutic agent that depletes or reduces B cells in the subject (claim 16), wherein the first therapeutic agent is administered after the transplant (claim 17b), and wherein the first therapeutic agent is administered one week after transplant (claim 18), Mohiuddin discloses the immunosuppressive regimen comprising administration of anti-CD20 antibody at day 7 post-transplant (Pg. 2, Table 1).
Regarding claims 26-27, wherein the first therapeutic agent is rituximab (claim 26), and wherein the rituximab is administered at a dosage of about 250 mg/m2 to about 500 mg/m2, Mohiuddin discloses the anti-CD20 antibody is Rituxan® (tradename for rituximab) administered at 19 mg/kg. Using the conversion provide in Nair for a 12kg baboon, the dose converts to 380 mg/m2 (19 mg/kg x 20, see Nair Table 1). Mohiuddin teaches the baboons of the disclosure ranged from 7-15 kg (Pg. 8 Methods, Animals).
Regarding claims 29-31 and 41, wherein the method of claim 1 further comprises administering a second therapeutic agent that depletes or reduces T cells in the subject (claim 29), wherein the second therapeutic agent is administered prior to the transplant (claim 30a), wherein the second therapeutic agent is administered from about 10 hours to about 24 hours prior to the transplant (claim 31), and wherein the second therapeutic agent is anti-thymocyte globulin, Mohiuddin discloses the immunosuppressive regimen comprising administration of anti-thymocyte globulin (“ATG”) at day -1 of the transplant (Pg. 2, Table 1).
Regarding claim 42, wherein the antibody or antigen- binding fragment thereof is administered at a dosage of about 10 mg/kg, Mohiuddin teaches maintenance administration of the anti-CD40 antibody at 10 mg/kg (Pg. 2, Table 1).
Regarding claims 43 and 46-47, wherein the transplant comprises a xenograft transplant (claim 43c), the xenograft transplant comprises a portion from a pig (claim 46), and wherein the xenograft transplant comprises a porcine heart (claim 47), the method of Mohiuddin comprises a cardiac xenograft with baboons receiving porcine hearts (Pg. 2, Left column, Full paragraph 2, Lines 1-2).
Regarding claim 49, wherein the method of claim 1 further comprises administering an anti-inflammatory agent, Mohiuddin teaches the regimen comprises administration of Solu-Medrol ®, identified in Table 1 as having the purpose of suppressing inflammation (Table 1, Pg. 2)
Regarding claim 4, pertaining to a method of treating or reducing a risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a human subject receiving or having received a transplant comprising administering a humanized anti-CD40 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising a CDRH1, CDRH2, and CDRH3 as set forth SEQ ID NOs: 1-3, respectively, and a light chain variable region comprising a CDRL1, CDRL2, and CDRL3 as set forth in SEQ ID NOs: 4-6, respectively, and wherein the antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously at a dosage of about 1 mg/kg to about 20 mg/kg, Mohiuddin teaches administration of the antibody 2C10R4 at a dose of 10-50 mg/kg during maintenance after transplant (Pg. 2, Table 1).
Regarding claims 8-9 and 13, wherein the antibody or antigen binding fragment of the method of claim 4 is administered prior to the transplant (claim 8), from about 10 hours to 24 hours prior to the transplant (claim 9), and one day after the transplant (claim 13), Mohiuddin teaches the anti-CD40 antibody is administered at day -1 and day 1 post-transplant (Pg. 2, Table 1).
Claim Rejections - 35 USC § 103
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 1-2, 4-6, 8-9, 13, 16-18, 26-27, 29-31, 41-43, 46-47, 49, 70-71, 100-102, and 104-106 are rejected under 35 U.S.C. 103 as being unpatentable over by Mohiuddin (Nat Commun. 2016 Apr 5;7:11138, IDS 06/02/2023) as applied to claims 1-2, 4, 8-9, 13, 16-18, 26-27, 29-31, 41-43, 46-47, and 49 in the 35 U.S.C. 102 rejection above, and further in view of Yu (2018/0078640A1, published 05/22/2018, IDS 06/02/2023).
The disclosure of Mohiuddin teaches an immunosuppressive regimen as part of a xenotransplantation protocol, the regimen comprising an induction phase with anti-CD40 antibody administration on days -1, 0, and 1 post-transplant (Pg. 2, Table 1) wherein the anti-CD40 antibody is a primitazed anti-CD40 monoclonal antibody 2C10R4, derived from murine clone 2C10 (Pg. 2, Right column.
Regarding claim 70, pertaining to a method of treating or reducing a risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a human subject receiving or having received a transplant comprising: (a) administering intravenously or subcutaneously an induction dose of an anti-CD40 antibody or antigen-binding fragment thereof, comprising a first dose of about 1 mg/kg to about 20 mg/kg from about 10 hours to about 24 hours prior to the transplant and a second dose of about 1 mg/kg to about 20 mg/kg, after the transplant once the subject achieves hemostasis; and (b) administering subcutaneously or intravenously a maintenance dose of the anti-CD40 antibody or antigen-binding fragment thereof at a dosage of about 1 mg/kg to about 20 mg/kg for treatment period of at least one month, Mohiuddin teaches intravenous administration of anti-CD40 in induction phase at day -1, 0, and 1 and weekly maintenance doses at 10-50 mg/kg.
Regarding claim 71, wherein the maintenance dose is provided to maintain a minimum blood, plasma, or serum concentration of the anti-CD40 antibody or antigen-binding fragment thereof of at least 150 pg/ml, Mohiuddin teaches in their protocol that the serum level of anti-CD40 antibody remains above 150 pg/ml during the maintenance phase (Fig. 2b).
Regarding claim 100, pertaining to the method of treating or reducing a risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a human subject receiving or having received a transplant comprising administering intravenously an anti-CD40 antibody induction dose and maintenance doses, Mohiuddin teaches induction dose of anti-CD40 antibody at days -1, 0, and 1 post-transplant (Pg. 2, Table 1).
Regarding claim 101, wherein the maintenance dose of the method of claim 100 is provided to maintain a minimum blood, plasma, or serum concentration of the anti-CD40 antibody or antigen-binding fragment thereof of at least 10 pg/ml, Mohiuddin teaches that in their protocol the serum level of anti-CD40 antibody remains above 10 pg/ml during the maintenance phase (Fig. 2b).
Regarding claim 102, wherein the method of claim 100 further comprises a third and/or fourth induction dose of about of the antibody or antigen-binding fragment thereof within about 1 day to about 14 days after the second induction dose, Mohiuddin teaches a third induction dose administered 1 day after the second dose (Pg. 2, Table 1).
Regarding claim 104, pertaining to a method of treating or reducing a risk of transplant rejection or increasing a duration of time before transplant rejection occurs in a human subject receiving or having received a transplant comprising:(a) administering intravenously or subcutaneously an induction dose of an anti-CD40 antibody or antigen-binding fragment thereof, comprising a conditioning dose of about 1 mg/kg to about 20 mg/kg from about 10 hours to about 24 hours prior to the transplant and a first induction dose of about 1 mg/kg to about 20 mg/kg, at a time post-transplant and after hemostasis has been achieved; and (b) administering subcutaneously or intravenously a maintenance dose of the anti-CD40 antibody or antigen-binding fragment thereof at a dosage of about 1 mg/kg to about 20 mg/kg for treatment period of at least one month, Mohiuddin teaches intravenous administration of anti-CD40 antibody at day -1 prior to transplant, day 1 post-transplant and during maintenance period at a dose of 10-50 mg/kg.
Regarding claim 105, wherein the method of claim 104 further comprises at least one more induction dose, the immunosuppressive regimen comprises three doses in the induction phase (Pg. 2, Table 1).
Regarding claim 106, wherein the maintenance phase of the method of claim 104 is initiated once the PK of the anti-CD40 antibody or antigen-binding fragment thereof is replicable or predictable, Mohiuddin teaches repeated sampling and determination of the serum level of the antibody in the subjects’ serum during the induction phase of the method, prior to the commencement of the maintenance phase (Fig. 2b).
Mohiuddin does not teach the following limitations:
The antibody comprises a heavy chain variable region set forth in SEQ ID NO:7 and a light chain variable region set forth in SEQ ID NO:8 (claims 5 and 6)
The primary dose any subsequent induction doses are at 1-20 mg/kg (claims 70-71, 100-102, 104-106)
These deficiencies are taught by Yu.
The disclosure of Yu is directed to the generation of humanized anti-CD40 antibodies and provides for a method of treating or treating prophylactically transplant rejection or increasing the duration of time before transplant rejection occurs comprising the step of administering to the subject an effective amount of the present antibody ([0030], Lines 1-6).
Regarding claims 5 and 6, wherein the heavy chain variable region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7, and wherein the light chain variable region comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 8 (claim 5) or wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 7, and wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8 (claim 6), Yu teaches discloses the humanized 2C10 antibody clone with the heavy chain variable region SEQ ID NO:21 identical to instant SEQ ID NO:7 and light chain variable region SEQ ID NO:23 identical to instant SEQ ID NO:8. The alignment is shown below:
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Regarding the limitation of claims 70-71, 100-102, 104-106, wherein the primary dose of the methods and subsequent induction doses are at 1-20 mg/kg, Yu teaches administration of the humanized anti-CD40 antibody clone 2C10 at 10 mg/kg, providing evidence that the 10 mg/kg dose did not deplete the lymphocyte population (Fig. 18, [0064]) and fully saturated CD40 binding sites on B cells (Fig. 19, [0065]). Importantly, Fig. 19 compares CD40 binding between a dosing at 25 mg/kg and 10 mg/kg, demonstrating that the CD40 binding sites were fully saturated at the lower dose 10 mg/kg.
It would have been obvious to one having ordinary skill in the art to modify the transplant immunosuppressive regimen of Mohiuddin by (1) using the humanized anti-CD40 2C10 clone with heavy and light chain variable regions set forth in SEQ ID NOs:7 and 8, respectively and (2) administration of the antibody in the induction phase at a dose of 10 mg/kg. One would have been motivated to do so because Mohiuddin’s preclinical immunosuppressive regimen is ultimately intended for use in human patients and Yu provides the humanized version of the 2C10 clone with evidence that a dose of 10 mg/kg is sufficient for fully saturating CD40 receptors on B cells. There would be an expectation of success in modifying the methods of Mohiuddin with the humanized anti-CD40 antibody at 10 mg/kg as taught by Yu because Yu provides in vivo evidence of the ability of the antibody to specifically saturate CD40 receptors on B cells.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671