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 .
Claims 1-10, 15, 16, 18, 20, 22, 27-29, and 31 are pending and currently under consideration.
Claim Objections
Claim 8 is objected to because of an apparent typographical error. The capitalized term “Optionally” in the last line of the claim should be replaced with “optionally”. Proper correction is required.
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.
Claims 1-10, 15, 16, 18, 20, 28, and 29 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.
Claims 1-10, 15, 16, 18, 20, 28, and 29 are rejected because claim 1 recites a second protein functional region targeting PD-L1 or PD1, wherein the second protein functional region is “an anti-PD-L1 antibody, an anti-PD-1 antibody, an anti-CTLA-4 antibody or an anti-HER-2 antibody, or an antigen-binding fragment thereof.” It is clear what is meant by anti-PD-L1 antibody, an anti-PD-1 antibody, or an antigen-binding fragment thereof that is a second protein functional region targeting PD-L1 or PD-1. However, the metes-and-bounds of the claims are unclear because it is unclear what is meant by “an anti-CTLA-4 antibody or an anti-HER-2 antibody, or an antigen-binding fragment thereof” that is a second protein functional region targeting PD-L1 or PD-1 because it is unclear, in what way, an anti-CTLA-4 antibody, an anti-HER-2 antibody, or an antigen-binding fragment thereof would (or would not) be considered to be “targeting” PD-L1 or PD-1 because such antibodies specifically bind other targets.
Claims 2-10, 15, 16, 20, and 28 are rejected because claims 2-10, 15, 16, 20, and 28 recite “preferably”, “e.g.”, and/or “such as”. The metes-and-bounds of the claims are unclear because it is unclear how, or if, text following “preferably” and “such as” limits the claims. Further, it is unclear how, or if, text in parenthesis with “e.g.” limits the claims.
Claim 10 recites “…wherein the first peptide chain and the second peptide chain….” There is insufficient antecedent basis for “the first peptide chain” and “the second peptide chain” in the claim.
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.
Claims 20 and 28 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 methods of “treating” a tumor comprising administering a bispecific antibody that targets 4-1BB and PD-L1 or PD-1, does not reasonably provide enablement for methods of “preventing” a tumor comprising administering a bispecific antibody that targets 4-1BB and PD-L1 or PD-1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in Ex parte Forman, 230 USPQ 546 (BPAI 1986). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed.
The instant claims are drawn to methods of “treating or preventing” a tumor comprising administering a bispecific antibody that targets 4-1BB and PD-L1 or PD-1. This includes prophylactic methods of preventing tumors in subjects that do not have tumors by administering recited bispecific antibodies.
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The specification discloses methods of “treating” a tumor comprising administering a bispecific antibody that targets 4-1BB and PD-L1 or PD-1 (examples 10-12, in particular). The specification does not demonstrate, and the art does not teach, recited antibodies are capable of “preventing” any tumor.
Reasonable guidance with respect to preventing any cancer or tumor relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to particular types of cancer. This type of data might be derived from widespread genetic analysis, cancer clusters, or family histories. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent.
One cannot extrapolate the teachings of the specification to the scope of the claims because the claims are broadly drawn to methods of “treating or preventing” a tumor comprising administering a bispecific antibody that targets 4-1BB and PD-L1 or PD-1, and Applicant has not enabled said methods because it has not been shown that recited antibodies are capable of “preventing” any tumor. Further, undue experimentation would be required to generate bispecific antibodies encompassed by the claims and determine which, if any, of said antibodies prevent tumors in order to perform the method as claimed.
In view of the teachings above and the lack of guidance, workable examples and or exemplification in the specification, it would require undue experimentation by one of skill in the art to determine with any predictability, that the method would function as 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3-5, 7-9, 15, 16, 18, 20, 22, 27-29, and 31 is/are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Wan et al (CN110627906B; 12/31/2019; 5/8/23 IDS).
Figure 3 of Wan et al teaches the following recombinant bispecific antibody proteins comprising single-domain nanobody (VHH) binding regions that target 4-1BB and PD-L1 (note that N-terminal is at the top of the drawings and C-terminal is at the bottom of the drawings):
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Wan et al further teaches the bispecific antibodies are to exert anti-tumor effects (see 1st paragraph above SUMMARY OF INVENTION at the google patents English translation: https://patents.google.com/patent/CN110627906B/en?oq=cn110627906). Wan et al further teaches said bispecific antibodies wherein the Fc is an Fc segment of IgG4 (see 8th paragraph under SUMMARY OF INVENTION at the English translation). Wan et al further teaches said bispecific antibodies conjugated to a detectable label (see the “eighth aspect” of the invention under the SUMMARY OF INVENTION of the English translation, in particular). Wan et al further teaches a kit comprising said conjugated bispecific antibodies (see the “eighteenth aspect” of the invention under the SUMMARY OF INVENTION of the English translation, in particular). Wan et al further teaches a pharmaceutical composition comprising said bispecific antibodies and a pharmaceutically acceptable carrier (see the “tenth aspect” of the invention under the SUMMARY OF INVENTION of the English translation, in particular). Wan et al further teaches a treatment method comprising administering to a subject in need thereof an effective amount of said bispecific antibodies (see the “sixteenth aspect” of the invention under the SUMMARY OF INVENTION of the English translation, in particular).
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, 3-5, 7-9, 15, 16, 18, 20, 22, 28, 29, and 31 are rejected under 35 U.S.C. 103(a) as being unpatentable over Bernett et al (US 2018/0127501 A1; 5/10/2018; 5/8/23 IDS) in view of Nie et al (Antibody Therapeutics, 2020, 3(1): 18-62) and Farrington et al (The FASEB journal, 2014, 28: 4764-4778).
Bernett et al teaches checkpoint inhibitor antagonistic antibodies bind PD-1 or PD-L1 to remove inhibitory signals holding back tumor-reactive T cells from tumor cell killing ([0004], in particular) and agonist antibodies that bind costimulatory proteins are a second approach for de-repressing tumor-reactive T cells ([0005], in particular). Bernett et al further teaches bispecific antibodies that bind costimulatory proteins (such as 4-1BB) and checkpoint inhibitors (such as PD-1 or PD-L1) for treating cancer ([0006]-[0010], in particular). Bernett et al further teaches pharmaceutical compositions comprising the bispecific antibodies and a pharmaceutically acceptable carrier ([0711], in particular) and methods of administering said pharmaceutical compositions ([0669], in particular).
Bernett et al does not specifically teach single-domain antibody constructs. However, these deficiencies are made up in the teachings of Nie et al and Farrington et al.
Nie et al is a review article that illustrates bispecific antibody building blocks (including single-domain VHH antigen-binding domains and Fc domains) and numerous possible structures of bispecific antibodies where domains are linked to one another (Figure 2, in particular). Nie et al further illustrates fusion sites for linking antigen-binding domains on Fc domains used to make bispecific antibodies (Figure 3A, in particular). Nie et al further teaches engineering Fc domains of bispecific antibodies to comprise mutations (such as knob-into-hole or electrostatic steering mutations) to facilitate heterodimeric association (right column on page 39, in particular). Nie et al further teaches IgG2 and IgG4 as sources of Fc domains of bispecific antibodies (right column on page 51, in particular).
Farrington et al teaches single-domain VHHs are small, monomeric antigen-binding antibody fragments with “excellent biophysical properties suitable as building blocks for multifunctional molecules…including fusions with hFc domains and bispecific antibodies (right column on page 4772, in particular). Figure 1 of Farrington et al illustrates the following bivalent antibody structure, comprising single-domain VHH binding domains and Fc:
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One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of generating and administering to cancer patients pharmaceutical compositions of Bernett et al comprising bispecific antibodies wherein the bispecific antibodies comprise single-domain VHHs that (i) bind an enhance activity of costimulatory protein 4-1BB and (ii) bind and inhibit checkpoint inhibitor PD-1 or PD-L1 because Bernett et al teaches bispecific antibodies that bind costimulatory proteins (such as 4-1BB) and checkpoint inhibitors (such as PD-1 or PD-L1) for treating cancer ([0006]-[0010], in particular), Bernett et al teaches checkpoint inhibitor antagonistic antibodies bind PD-1 or PD-L1 to remove inhibitory signals holding back tumor-reactive T cells from tumor cell killing ([0004], in particular) and agonist antibodies that bind costimulatory proteins are a second approach for de-repressing tumor-reactive T cells ([0005], in particular), Nie et al teaches binding domains of bispecific antibodies include single-domain VHHs (Figure 2, in particular), and Farrington et al teaches single-domain VHHs are small, monomeric antigen-binding antibody fragments with “excellent biophysical properties suitable as building blocks for multifunctional molecules…including fusions with hFc domains and bispecific antibodies (right column on page 4772, in particular). This is an example of a simple substitution of single-domain VHH binding domains in place of the binding domains of bispecific antibody of Bernett et al to predictably result in a bispecific antibody comprising single-domain VHH binding domains.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said combined method wherein the bispecific antibodies comprise any bispecific antibody general structure encompassed by Figure 3A of Nie et al, including that of Figure 1 of Farrington et al, using just any IgG Fc domain (including IgG2 or IgG4 of Nie et al) because Nie et al further illustrates fusion sites for antigen-binding domains on Fc domains used to make bispecific antibodies (Figure 3A, in particular) and Farrington et al demonstrates bispecific antibodies with such structures. This is an example of combining prior art elements according to known methods to yield predictable results.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to supply the reagents of the method as a kit because generating a “kit” for a given method provides two services: 1) a variety of different reagents have been assembled and pre-mixed specifically for a defined set of experiments. Thus, one need not purchase gram quantities of numerous different reagents when each of which may be needed in only microgram amounts, when beginning a series of experiments. When one considers all of the unused chemicals that typically accumulate in weighing rooms, desiccators, and freezers, one quickly realizes that it is actually far more expensive for a small number of users to prepare most buffer solutions from the basic reagents. In actuality, a kit format saves money and resources for everyone by dramatically reducing waste. 2) The other service provided in a kit is quality control. Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to combine the reagents of a method into a kit format since a kit provides a quality control, saves money, and saves resources.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1, 3-9, 15, 16, 18, 20, 22, 27-29, and 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wan et al (CN110627906B; 12/31/2019; 5/8/23 IDS) as applied to claims 1, 3-5, 7-9, 15, 16, 18, 20, 22, 27-29, and 31 above, and further in view of Wu et al (US 2018/0371088 A1; 12/27/18).
Teachings of Wan et al are discussed above.
Wan et al does not specifically teach Fc regions of the bispecific construct comprise L234A/L235A and G237A mutations. However, these deficiencies are made up in the teachings of Wu et al.
Wu et al teaches L234A/L235A and G237A Fc mutations result in diminished non-specific effector functions (such as ADCC and CDC) of antibody constructs used in therapies where the antibodies are to target cells, as opposed to being used to just generate effector functions ([0004]-[0010] and [0050], in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate and administer the bispecific construct with Wan et al wherein the construct has L234A/L235A and G237A Fc mutations because the bispecific construct is intended to bind therapeutically PD-L1 and 4-1BB and is not taught to be used to generate non-specific effector functions and Wu et al teaches L234A/L235A and G237A Fc mutations result in diminished non-specific effector functions (such as ADCC and CDC) of antibody constructs used in therapies where the antibodies are to target cells, as opposed to being used to just generate effector functions ([0004]-[0010] and [0050], in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1, 3-9, 15, 16, 18, 20, 22, 28, 29, and 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bernett et al (US 2018/0127501 A1; 5/10/2018; 5/8/23 IDS) in view of Nie et al (Antibody Therapeutics, 2020, 3(1): 18-62) and Farrington et al (The FASEB journal, 2014, 28: 4764-4778) as applied to claims 1, 3-5, 7-9, 15, 16, 18, 20, 22, 28, 29, and 31 above, and further in view of Wu et al (US 2018/0371088 A1; 12/27/18).
Teachings of Bernett et al, Nie et al, and Farrington et al are discussed above.
Bernett et al, Nie et al, and Farrington et al do not specifically teach Fc regions of the bispecific construct comprise L234A/L235A and G237A mutations. However, these deficiencies are made up in the teachings of Wu et al.
Wu et al teaches L234A/L235A and G237A Fc mutations result in diminished non-specific effector functions (such as ADCC and CDC) of antibody constructs used in therapies where the antibodies are to target cells, as opposed to being used to just generate effector functions ([0004]-[0010] and [0050], in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate and administer the bispecific construct of the combined method of Bernett et al, Nie et al, and Farrington et al wherein the construct has L234A/L235A and G237A Fc mutations because the bispecific construct is intended to inhibit PD-1 or PD-L1 and activate 4-1BB and is not taught to be used to generate non-specific effector functions and Wu et al teaches L234A/L235A and G237A Fc mutations result in diminished non-specific effector functions (such as ADCC and CDC) of antibody constructs used in therapies where the antibodies are to target cells, as opposed to being used to just generate effector functions ([0004]-[0010] and [0050], in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
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/SEAN E AEDER/Primary Examiner, Art Unit 1642 82