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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/JP2021/020334 filed May 28, 2021.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Foreign priority is claimed through JAPAN 2020-093777 filed on May 28, 2020. The certified copy has been filed in the instant application on November 21, 2022; however, no English translation has been provided (MPEP § 213.04). Therefore, all claims have been given an effective filing date of May 28, 2021.
Election/Restriction
Applicant's species election without traverse of:
R at position 200 (option 16)
L at position 44, E at position 48, P at position 155, L at position 172, I at position 175, and R at position 200 (option b)
in the reply filed on October 22, 2025 is acknowledged.
Upon further consideration, Examiner withdraws the restriction requirement among species A and B as set forth in the Office action mailed on 09/05/2025. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Claim Status
Claim listing filed on June 15, 2023 is pending. Claims 1-23 are canceled. Claims 24-53 are new. Claims 24-53 are examined upon their merits.
Information Disclosure Statement
The information disclosure statements filed on 01/30/2023, 06/06/2024, 08/05/2024, and 08/27/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 24, 28, 41, and 50-51 are objected to because of the following informalities:
Claims 24, 28, 41, and 51 have numerical sub-parts (1, 2, 3) where all other claim sub-parts are listed alphabetically (a, b, c). For consistency and clarity, list the sub-parts of Claims 24, 28, 41, and 51 alphabetically.
Claim 50 lists sub-parts alphabetically starting with “x” (x, y). For consistency and clarity, list the sub-parts of Claim 50 alphabetically starting with “a” (a, b).
Appropriate 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.
Claims 40, 43-45, and 50-53 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 40 recites “wherein the granzyme B variant has higher protease activity and greater resistance to a granzyme B inhibitor compared to a human wild-type granzyme B having an amino acid sequence consisting of SEQ ID NO: 1.” Claims 43-45, 50, and 53 are dependent on Claim 40 and do not further define the claimed granzyme B variant. This phrase is considered functional language because the feature (the granzyme B variant) is defined by what it does (has higher protease activity and greater resistantance to a granzyme B inhibitor) rather than by what it is (MPEP § 2173.05(g)). To determine if functional language is ambiguous, the following factors are considered: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim. These factors are examples of points to be considered when determining whether language is ambiguous and are not intended to be all inclusive or limiting (MPEP § 2173.05(g)). Claim 40 is directed to results obtained without any required structure for the granzyme B variant. The metes about bounds of the granzyme B variants cannot be readily determined. Therefore, Claims 40, 43-45, 50, and 53 are rejected as being indefinite.
Claim 43 recites “wherein the receptor, when bound it its ligand, activates the cell expressing the receptor.” This phrase is considered functional language because the feature (the receptor) is defined by what it does (activates the cell expressing the receptor) rather than by what it is (MPEP § 2173.05(g)). Claim 43 is directed to a result obtained without any required structure for the receptor. The metes about bounds of the receptor cannot be readily determined, and Claim 43 is rejected as being indefinite.
Claim 50 recites “an antigen-binding molecule that binds to a target antigen expressed on a target cell.” This phrase is considered functional language because the feature (the molecule) is defined by what it does (binds an antigen) rather than by what it is (MPEP § 2173.05(g)). Claims 51-53 are dependent on Claim 50 and do not further define the claimed molecule. Claim 50 is directed to a result obtained without any required structure for the molecule. The metes about bounds of the molecule cannot be readily determined, and Claims 50-53 are rejected as being indefinite.
Note, the relative terms “higher” and “greater” in Claims 26 and 40 are not indefinite because protease activity with and without the presence of a granzyme B inhibitor can be measured and compared to human wild-type granzyme B by means understood in the art prior to the time of filing. It is interpreted with the broadest reasonable interpretation that any increase (even a non-significant change) is encompassed by the terms “higher” and “greater.” Note, Claims 26-27 are interpreted as inherent properties of the granzyme B structures recited in Claim 25 (MPEP § 2112.01).
Note, the functional language encompassed by “extracellular binding domain,” “transmembrane domain,” and “intracellular signaling domain” in Claims 44, 46, 48, 50, and 53 as defined in specification paragraphs [0031]-[0033] is not indefinite because the structural components of a chimeric antigen receptor (CAR) were well understood in the art prior to the time of filing as evidenced by Darowski et al. MABS 2019 (page 622, paragraph 2 and Fig. 1).
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.
Claims 25-27, 29, 31, 33, 35, 37, 39, and 48-49 are 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.
Claims 25 and 29 recite a granzyme B variant comprising E at position 48 (Claims 25(b), 25(d), 29(b), and 29(d)). However, Claims 25 and 29 depend from Claims 24 and 28 respectively, and Claims 24 and 28 define wherein position 48 can be mutated to F, mutated to K, or maintain the wildtype residue R. In summary, Claims 24 and 28 define wherein position 48 can be three possible amino acids (F, K, or R), but Claims 25 and 29 define wherein position 48 can be amino acid E. Therefore, Claims 25 and 29 fail to include all the limitations of the claims upon which they depend. 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.
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.
Claims 24, 28, 30, 32, 34, 36, 38, 40-41, 43-47, 50-51, and 53 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 claims contain 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.
Claims 24, 28, 41, and 51 recite a granzyme B variant comprising one or more amino acid residues selected from options (1)-(20). The granzyme B variant can comprise any combination of amino acid mutations listed in (1)-(20) which includes up to 20 total mutations and results in a genus of possible granzyme B variants. Claim 40 is directed to an even broader genus of granzyme B variants comprising any variant that has higher protease activity and greater resistance to a granzyme B inhibitor as compared to a human wild-type granzyme B. Claim 43 recites further administering any cell expressing any receptor which results in a broad genus of possible cells.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. In order to provide adequate written description and evidence of possession of this claimed genus of agents, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
In the instant case, the specification teaches 33 granzyme B variants comprising a single mutation that have increased protease activity relative to wild-type granzyme B (paragraph [0052] and Fig. 2). Further, the specification teaches 12 granzyme B variants comprising a combination of five mutations that have increased protease activity relative to wild-type granzyme B, even in the presence of inhibitors (paragraph [0052], Table 1, and Fig. 3). The specification teaches the cytotoxic activity of T cells transfected with the granzyme B variants (Example 10) but fails to teach any examples of therapeutically administering cells expressing a receptor wherein the receptor activates the cell when bound to its ligand. Twelve species of granzyme B variants each comprising 5 mutations do not adequately describe the genus of granzyme B variants that can comprise any combination of the mutations up to 20 substitutions.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (MPEP § 2163.05.Ib). In the absence of sufficient recitation of distinguishing identifying characteristics or structure-to-function attributes for the entire genus of granzyme B variants, the specification does not provide adequate written description of the claimed genus. Therefore, in view of the case law directed to an appropriate number of representative species, claims 24, 28, 30, 32, 34, 36, 38, 40-41, 43-47, 50-51, and 53 are rejected for insufficient written description.
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).
Claims 24, 28, 30, 32, 34, 36, 38, 40-41, 43-47, 50-51, and 53 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 the specific species of granzyme B variants listed in Figs. 2-3, does not reasonably provide enablement for the genus of granzyme B variants encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
MPEP § 2164.01(a) states that 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, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention:
The nature of the invention is complex. As understood with the broadest reasonable interpretation, Claims 24, 28, 41, and 51 are directed to a genus of granzyme B variants comprising any combination of amino acid mutations listed in (1)-(20) which includes up to 20 total mutations. Claim 40 is directed to an even broader genus of granzyme B variants comprising any variant that has higher protease activity and greater resistance to a granzyme B inhibitor as compared to a human wild-type granzyme B. Claim 43 recites further administering any cell expressing any receptor which results in a broad genus of possible cells.
When analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be "given their broadest reasonable interpretation consistent with the specification." See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
The state of the prior art and level of predictability in the art:
The level of predictability in the art depends, most importantly, on whether the claimed invention can be practiced by one of ordinary skill in the art. In AMGEN INC. ET AL. v. SANOFI ET AL. (No. 21-757, decided May 18, 2023), the Supreme Court held that Amgen was not enabled for “the entire genus” of antibodies that (1) “bind to specific amino acid residues on PCSK9,” and (2) “block PCSK9 from binding to [LDL receptors]” (872 F. 3d 1367, 1372) even though Amgen identified the amino acid sequences of 26 antibodies that perform these two functions. The case law applies to the instant claims which encompass a genus of granzyme B variants that have required function, yet the inventors have only disclosed 12 species of granzyme B variants comprising multiple mutations that the required protease activity (Table 1).
In Amgen, the Supreme Court has stated that despite recent advances, aspects of antibody science remain unpredictable. For example, scientists understand that changing even one amino acid in the sequence can alter an antibody's structure and function. See id., at 14. But scientists cannot always accurately predict exactly how trading one amino acid for another will affect an antibody's structure and function. Ibid. The unpredictability of polypeptide structure and function extends to the granzyme B variants in the instant application. It is unclear how combining different amino acid mutations will affect the required protease function.
The case law shows a continued lack of predictability even after the effective filing date of the instant invention, and there is no support in the Applicant’s disclosure leading one of ordinary skill to overcome the lack of predictability in the genus of granzyme B variants claimed. The specification provides no guidance or direction for structure that must be maintained such that the functional properties of the invention are preserved (higher protease activity and greater resistance to an inhibitor).
Further, nothing in the art prior to filing supports administering any type of cell comprising any type of receptor for the treatment of cancer (Claim 43). For example, administering mesenchymal stromal cells is known to treat autoimmune disorders, cardiovascular disease, and neurological disorders but is not a standard cancer treatment. Not all therapeutic cells have anti-cancer activity.
Level of skill in the art:
The level of skill would be high encompassing protein science, enzyme activity assays, oncology treatment, etc.
Amount of direction provided by inventor and the existence of working examples:
The specification teaches 33 granzyme B variants comprising a single mutation that have increased protease activity relative to wild-type granzyme B (paragraph [0052] and Fig. 2). Further, the specification teaches 12 granzyme B variants comprising a combination of five mutations that have increased protease activity relative to wild-type granzyme B, even in the presence of inhibitors (paragraph [0052], Table 1, and Fig. 3). The specification teaches the cytotoxic activity of T cells transfected with the granzyme B variants (Example 10) but fails to teach any examples of therapeutically administering cells expressing a receptor wherein the receptor activates the cell when bound to its ligand.
Twelve species of granzyme B variants comprising five mutations each do not adequately represent the scope of variants that can comprise any combination of amino acid mutations listed in (1)-(20) which includes up to 20 total mutations. A person having ordinary skill in the art would have to make a substantial inventive contribution in order to make and characterize a representative number of granzyme B variants and use them in the method of treating cancer to encompass the claimed genus.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
In light of the unpredictability surrounding the claimed subject matter, the undue breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to make and practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Given that structure is essential to function, a person having ordinary skill in the art would have to perform further experimentation to make the granzyme B variants encompassed by the claims and screen their protease activity and anti-cancer activity in order to practice the invention commensurate with the scope of the claims.
The instant specification does not enable the invention to make and use the entire genus of granzyme B variants, and Claims 24, 28, 30, 32, 34, 36, 38, 40-41, 43-47, 50-51, and 53 are rejected.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 24, 28, 30, 32, 34, 36, and 38 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Specifically, the instant claims encompass a product of nature.
Claim 24 recites a granzyme B variant comprising an R at position 200 wherein the position numbers correspond to positions in SEQ ID NO: 1. The specification defines that “granzyme B” refers to any wild-type granzyme B from any vertebrate source including mammals such as primates and rodents (paragraph [0017]). The specification also states: “Even if the amino acid sequence of granzyme B to be altered has part different from the sequence shown in SEQ ID NO: 1, those skilled in the art can appropriately determine where the positions of alterations shown herein actually correspond to in granzyme B to be altered (e.g. by performing sequence alignment)” (page 13, paragraph 3).
UniProt (entry P18291 submitted April 10, 2019) teaches the amino acid sequence of granzyme B produced naturally in rats (last paragraph, 248 amino acids in length). The sequence alignment below compares instant SEQ ID NO: 1 (human wild-type granzyme B) on the top line with rat wild-type granzyme B on the bottom line. As highlighted in blue, rat granzyme B naturally has a R residue at position 201 which corresponds to R at position 200 of instant SEQ ID NO: 1 and reads on Claim 24 sub-claim (16).
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Therefore, a granzyme B variant comprising an R at position 200 corresponding to positions in SEQ ID NO: 1 is a product of nature. As proteins are naturally encoded by nucleic acid within cells, Claims 28, 32, and 34 are also directed to products of nature. These judicial exceptions are not integrated into a practical application because the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. Nothing beyond use of routine and conventional methods are encompassed by the claims in addition to the judicial exceptions (such as isolating the protein and/or nucleic acid in a vector or pharmaceutical composition in Claims 30, 36, and 38).
Therefore, claims 24, 28, 32, 34, 36, and 38 do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions.
The rationale for this determination is explained below:
The unpatentability of laws of nature/natural phenomenon was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 101 USPQ2d 1961 (March 20, 2012), and Association for Molecular Pathology v. Myriad Genetics, Inc. 106 USPQ2d 1972 (2013).
Accordingly, the issues are:
a) the current invention is directed to a granzyme B variant that is naturally produced in rats (Step 2A- Prong One - YES),
b) the current claims fail to recite a practical application of additional elements that integrate the judicial exception into a practical application. The claims, for example, are not directed to using the judicial exceptions to affect a particular treatment as discussed in MPEP § 2106.04(d)(2). (Step 2A- Prong Two - NO),
c) nothing significantly more than the judicial exceptions is recited within the claims. The courts have defined that simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to a judicial exception is not “significantly more” (MPEP § 2106.05.I.A). For example, the courts have recognized that using polymerase chain reaction to amplify and detect DNA and amplifying and sequencing nucleic acid sequences are routine activities in the life sciences when claimed at a high level of generality (MPEP § 2106.05(d).II). (Step 2B - NO).
In Mayo Collaborative Services it was held that:
"Phenomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work." Gottschalk v. Benson, 409 U. S. 63, 67 (1972). And monopolization of those tools through the grant of a patent might tend to impede innovation more than it would tend to promote it. [emphasis added].
In summary, a granzyme B variant comprising an R at position 200 corresponding to SEQ ID NO: 1 reads on granzyme B that is naturally produced in rats. Expressing the naturally-occurring nucleic acid as a vector or formulating the protein as a pharmaceutical composition utilize routine and conventional laboratory techniques that do not result in significantly more than the judicial exceptions.
For these reasons claims 24, 28, 30, 32, 34, 36, and 38 are rejected under section 101 as being directed to non-statutory subject matter.
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 24, 28, 32, and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by UniProt Rat Granzyme B (entry P18291 submitted April 10, 2019).
Claim 24 recites a granzyme B variant comprising an R at position 200 wherein the position numbers correspond to positions in SEQ ID NO: 1. The specification defines that “granzyme B” refers to any wild-type granzyme B from any vertebrate source including mammals such as primates and rodents (paragraph [0017]). The specification also states: “Even if the amino acid sequence of granzyme B to be altered has part different from the sequence shown in SEQ ID NO: 1, those skilled in the art can appropriately determine where the positions of alterations shown herein actually correspond to in granzyme B to be altered (e.g. by performing sequence alignment)” (page 13, paragraph 3). Claim 28 is directed to a nucleic acid encoding the granzyme B variant of Claim 24, Claim 32 recites a cell containing the nucleic acid of Claim 28, and Claim 34 recites a cell expressing the granzyme B variant of Claim 24.
UniProt teaches the amino acid sequence of granzyme B produced naturally in rats (last paragraph, 248 amino acids in length). Rat granzyme B has a R residue at position 201 which corresponds to R at position 200 of instant SEQ ID NO: 1 and reads on Claim 24 sub-claim (16) (see above sequence alignment in 101 rejection). As proteins are naturally encoded by nucleic acid within cells, the rat wild-type granzyme B amino acid sequence inherently anticipates Claims 28, 32, and 34.
Therefore, Claims 24, 28, 32, and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by UniProt.
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 24, 28, 30, 32, 34, 36, 38, 40-41, and 43-47 are rejected under 35 U.S.C. 103 as being unpatentable over Barth WO 2013/041659 (of record in IDS) in view of Wang WO 2018/045177 (of record in IDS).
In regard to Claims 24, 38, and 40-41, Barth teaches granzyme B variants that have increased activity and reduced sensitivity to inhibitors as compared to wildtype human granzyme B (page 3, lines 7-10). The granzyme B variants can be formulated as a pharmaceutical composition and administered to treat cancer (page 3, lines 27-30 and page 4, lines 13-21). The granzyme B variant comprises a R28K mutation corresponding to Barth SEQ ID NO: 1 (page 35, lines 1-32). Note, the R28K mutation corresponds to the R48K of instant SEQ ID NO: 1.
In regard to Claims 28, 30, 32, 34, and 36, Barth teaches a nucleic acid molecule that encodes the granzyme B variant (Claim 14), a vector comprising the nucleic acid molecule (Claim 15), a host cell comprising the vector and/or the nucleic acid molecule (Claim 16), and a host cell that expresses the granzyme B variant (Claim 18). The nucleic acid expression vector can be formulated as a pharmaceutical composition for therapeutic administration (page 23, lines 4-13 and page 24, lines 1-6).
Barth teaches that additional anticancer therapies may be used in combination or in conjunction with the granzyme B variants such as immunotherapy (page 23, lines 20-24). Barth fails to teach wherein the immunotherapy is specifically a chimeric antigen receptor (CAR) T-cell (Claims 43-47).
Wang teaches T-cells comprising CARs and transgene payloads (abstract and paragraph [00048]) that can be administered as pharmaceutical compositions to treat cancer (paragraphs [000175]-[000176] and [000224]). The transgene can encode a payload for delivery at the site of CAR activation, and the payload can be a cytotoxic compound such as a granzyme (paragraph [00010]). The CAR comprises an extracellular antigen-binding domain, a transmembrane domain that anchors the receptor to the cell membrane, and at least one intracellular signaling domain (paragraph [00097]). The extracellular domain can specifically bind tumor-associated antigens (paragraph [000101]).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to adapt the method of treating cancer by administering a granzyme B variant as taught by Barth to include administering the granzyme B variant in a CAR T-cell system as taught by Wang. Wang teaches that CAR T-cells can deliver granzymes that are released at the tumor site when the CAR is activated. The therapeutic strategy has a dual mechanism utilizing both immunotherapy (CAR T-cells) and cytotoxic therapy (granzymes). Barth teaches that granzyme B comprising a R28K mutation has increased activity and reduced sensitivity to inhibitors, highlighting the motivation to use the granzyme B variant instead of the wild-type granzyme B. One of ordinary skill could have applied the “improved” granzyme B variant of Barth to the CAR T-cell payload system of Wang, and the results would have been predictable.
Claims 50-51 and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Barth WO 2013/041659 (of record in IDS) and Wang WO 2018/045177 (of record in IDS) as applied to Claims 24, 28, 30, 32, 34, 36, 38, 40-41, and 43-47 above, and further in view of Darowski et al. MABS 2019 and Kavanaugh, Expert Opin Biol Ther. 2019.
The teachings of Barth and Wang as they apply to Claims 24, 28, 30, 32, 34, 36, 38, 40-41, and 43-47 are outlined in the rejection above and comprise administering CAR T-cells in combination with a granzyme B variant comprising a R28K mutation to treat cancer. Barth and Wang fail to teach further administering an antigen-binding molecule that binds to a target antigen on a target cell wherein the extracellular domain of the CAR binds to the antigen-binding molecule (Claim 50) or wherein the antigen-binding molecule comprises a protease cleavable linker (Claim 53).
Darowski teaches that universal or modCARs describe chimeric receptors that do not directly recognize the target antigen but instead make contact to adaptor molecules (CAR-adaptors) (page 622, paragraph 4). CAR-adaptors can be mAbs, antibody fragments, small molecules or any conceivable structure that is able to target at least one desired antigen, and that can simultaneously be recognized by the modCAR-T cells (page 622, paragraph 5 and Fig. 2). The modCAR system provides the opportunity to control the activity of CAR-T cells using the CAR-adaptors and allows the CAR-T cells to target a variety of antigens simultaneously without the need for re-engineering T cells (page 622, paragraph 1). Further, Kavanaugh teaches an antibody prodrug approach that has potent antitumor activity with improved safety (abstract). Kavanaugh teaches that antibody prodrugs comprise masks linked to the antibody by protease cleavable linkers, and when the prodrug enters the tumor microenvironment, upregulated proteases that are common in cancer tissues cleave the linker, the mask separates from the antibody, and the antibody becomes competent to bind to its target in the tumor (page 2, paragraph 2 and Fig. 1). This process does not happen efficiently in normal tissues because there is insufficient extracellular protease activity to remove the mask (page 2, paragraph 2).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to apply the modCAR system taught by Darowski (which reads on Claim 50) and the antibody prodrug system taught by Kavanaugh (which reads on Claim 53) to the method of treatment taught by Barth and Wang. The motivation to apply the modCAR system of Darowski to the CAR T-cells of Wang is because the CAR-adaptors provide better control and allow the CAR-T cells to target a variety of antigens simultaneously without the need for re-engineering T cells. The motivation to make the CAR-adaptors specifically an antibody prodrug comprising a protease cleavable linker as taught by Kavanaugh is for more targeted delivery with less unintended side effects because the antibody is specifically activated in the tumor microenvironment. One of ordinary skill could apply the known techniques to the known method of treatment to improve the targeted cancer therapy with predictable results.
Allowable Subject Matter
Claim 42 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Specifically, a method of treating cancer by administering any one of the granzyme B variants of Claim 42(a)-(l) is both enabled and free of the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571) 272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675