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 .
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that the Sequence Listing XML provided on February 6, 2024 provides 3 sequences. However, in addition to SEQ ID NOs 1-3, the specification refers to SEQ ID NOs 4-16 on at least pages 5, 51, and 59. These aforementioned SEQ ID NOs are not provided nor described in the accompanying Sequence Listing XML. Additionally, it is noted that the sequences in the current Sequence Listing XML do not match those provided in the text of the specification. Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Information Disclosure Statement
The information disclosure statement filed on May 6, 2024 is acknowledged and has been considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
On page 42, the bottom left structure is labeled as “Malevertinib,” but the examiner notes that this is known in the art by the name “Mavelertinib” instead.
On page 43, the last two structures of Table 1 are missing. In Table 2A, the first two structures (pg. 45) and last structure (pg. 47) are also missing. In Table 2B, the first two structures (pg. 47) and last structure (pg. 49) are missing. In Table 2C, the first two structures (pg. 49) and last structure (pg. 51) are also missing. These structures are also not present (not crossed out) in the marked up amended specification. The examiner notes that this may be a table formatting error hiding the structures previously present.
Appropriate correction is required.
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.
Claims 9, 10, and 69 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 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 9 requires a conjugate comprising a protein targeting ligand that forms a covalent bond with an intracellular mutated protein comprising a cysteine, wherein the intracellular protein is overexpressed compared to a corresponding wild-type protein. In the instant specification, the applicant provides three examples of proteins which may be the overexpressed protein in some embodiments (CRIP1, CRISP3, and CYR61) ([0139]). However, the examiner notes that in order for a ligand to “target” a protein, it is implied there is specificity for the ligand to bind to that protein instead of others. The examiner notes that the applicant is silent regarding core compound structures or recitations of names of compounds that could provide specificity for targeting overexpressed proteins beyond those provided in Table 1. However, the compounds in Table 1 are known to target FGFR, EGFR, BTK, JAK3, XPO1, and HER2 and that these are not described as overexpressed proteins in the instant specification. Therefore, no description of ligands that target specific mutant overexpressed proteins and covalently bond to a residue in said protein (or could be modified to do so) is provided. Instead, only a superficial discussion of the concept of ligands targeting mutant overexpressed proteins is provided. Furthermore, this lack of disclosure means that there is no discussion of how to prepare a conjugate comprising a ligand that targets an overexpressed mutant protein with a metal chelator. Thus, the examiner considers that conjugates comprising ligands that target overexpressed mutant proteins have not been described in the specification in a way to reasonably convey to one skilled in the art that the inventor, at the time the application was filed, had possession of the claimed invention of claim 69. Furthermore, as claim 10 depends upon claim 9 and does not narrow the scope in a way that avoids the aforementioned issues, claim 10 is also rejected for the above reasons.
Claim 69 requires a conjugate comprising a protein targeting ligand that forms a covalent bond with a lysine residue or a serine residue of an intracellular mutated protein. In the instant specification, the applicant provides some exemplary chemical structures used in the art to form covalent adducts between small molecules and serine ([0097]) and lysine ([0098]) residues on proteins. The applicant also states that the ligand may form a covalent bond with a serine or lysine residue on the listed proteins in [0141]-[0156] (including KRAS, FGFR3, EGFR, ERBB3, etc.). However, the examiner notes that in order for a ligand to “target” a protein, it is implied there is specificity for the ligand to bind to that protein instead of others. In covalent inhibitors, the same common “warhead” groups, such as those provided in [0097] and [0098], are used across different covalent inhibitors and are changed based on which amino acid is being targeted and may be optimized within the groups. Since the covalent bond forming portions of these molecules tend to be the same or similar to each other, the specificity of the molecule for a given protein is derived from the other structural components of the molecule that enable the key interactions with the binding pocket to be made. The examiner notes that the applicant is silent regarding core compound structures or recitations of names of compounds that could provide specificity for targeting proteins beyond those provided in Table 1. However, the compounds in Table 1 already contain electrophilic groups and are known to be cysteine-bonding ligands. Therefore, no description of ligands that target specific proteins and covalently bond to serine or lysine residues (or could be modified to do so) is provided. Instead, only a superficial discussion of the concept of serine and lysine bonding ligands is provided. Thus, the examiner considers that conjugates comprising ligands that target proteins and form covalent bonds with serine or lysine have not been described in the specification in a way to reasonably convey to one skilled in the art that the inventor, at the time the application was filed, had possession of the claimed invention of claim 69.
Claim 96 is 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 cancer wherein the targeting ligand of the conjugate of claim 1 targets a tumor associated protein and possesses its own anti-cancer properties or wherein the targeting ligand targets a tumor associated protein and the conjugated metal chelator group further comprises a radionuclide that can be used to treat cancer, does not reasonably provide enablement for methods of treating cancer wherein the targeting ligand of the conjugate of claim 1 does not target a tumor-associated protein or wherein the targeting ligand targets a tumor-associated protein but does not have anti-cancer effects on its own and the metal chelator lacks a radionuclide that can effectively be used to treat a cancer. 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/or use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. These factors include, but are not limited to:
The breadth of the claims;
The nature of the invention;
The state of the prior art;
The level of one of ordinary skill;
The level of predictability in the art;
The amount of direction provided by the inventor;
The existence of working examples; and
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427, F.2d 833, 839, 166 USPQ 18, 24 (1970). To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, state and predictability of the art, and relative skill level
The invention of claim 96 relates to methods of treating cancer using conjugates comprising a metal chelator, a linker, and a ligand that targets and covalently binds a mutated intracellular protein.
The relative skill of those in the art who would use such compounds is high, likely that of one who has obtained at a Ph.D. or M.D.
In the art, it is understood that in order to treat cancer via the administration of a compound to a subject in need thereof, the compound must possess properties that allow it to exert the desired pharmacological effect. This typically involves inhibiting pro-cancer signaling pathways and proteins and killing cells in a way that kills cancer cells more readily than non-cancerous cells are killed. Relating to the claimed invention, this may take the form of compounds that target tumor-associated proteins and inhibit them or kill the cell harboring said tumor-associated protein (either through cytotoxic effects of the ligand alone, downstream events caused by the binding event, or by inducing proximity of the tumor to a radiation-emitting radionuclide capable of damaging and/or killing the tumor cells). In the art of cancer treatment, it is known that not all proteins are tumor-associated and that not all metals or isotopes of metals are capable of exerting a cancer-treating effect.
There is generally a lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970). While predictions can be made regarding how ligands will bind receptors in silico, these are inconsistent at determining if a ligand will be able to exert a pharmacological effect in a living biological subject.
The breadth of the claims
Claim 96 is broad insofar as the claim allows for the method to be performed using any compound that fits within the scope of claim 1. Likewise, the scope of claim 1 is broad. The conjugate of claim 1 must contain a metal chelator, but the claim includes embodiments in which the metal chelator is not bound to a therapeutic radionuclide (or any atom at all). Additionally, claim 1 requires that the targeting ligand form a covalent bond with a mutated intracellular protein. The scope of this limitation includes many proteins that are not tumor-associated and many ligands that bind to a protein that do not possess anti-cancer effects.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides little direction or guidance for practicing the claimed invention in its “full scope.” No working examples are provided for the use of any compounds within the scope of claim 1 for the treatment of any cancer. Example B3 provides examples of inhibition of cell growth by conjugates containing KRas G13C inhibitors already known to independently possess anticancer properties independent of the chelator conjugation. The guidance provided for the practice of this method is very broad, such that it could apply to nearly all pharmaceutical compounds.
The quantity of experimentation necessary
Experimentation to determine a therapeutically or diagnostically effective amount of material to administer to a subject can be significant. Furthermore, determining if any given compound is effective for treatment of certain diseases may span long periods of time. Additionally, while there is an increasing number of covalent ligands being invented, determination that these ligands will also bind to mutant forms of proteins requires additional experimentation. It would require significant experimentation to determine how to use a conjugate comprising a ligand that targets a protein not associated with tumors for the use of treating cancer.
Because of the known state of the art, and in the absence of experimental evidence and working examples, it is apparent that the amount of experimentation required to determine which of the claimed structures of claim 1 could be used in the claimed methods of treatment would be efficacious is very significant and unreasonable due to the breadth of the peptide sequence being claimed.
Accordingly, the instant claims do not comply with the enablement requirement of §112(a), since to practice the claimed invention in its “full scope,” a person of ordinary skill in the art would have to engage in an unreasonable amount of experimentation, with no reasonable expectation of success.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 4, 8-12, 19, 35, 38, 40, 42, 69, 75, 81, 88, 94, 96, and 108 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “intracellular” in claims 1, 4, 8, 9, 12, 40, 42, 69, 108 is used by the claim to mean “a protein wherein any portion of the protein is present within the confines of a cell,” and appears to refer to the intracellular portions of proteins that are only partially present inside cells while the accepted meaning is “a protein wherein the entirety of the protein is present inside the outer barrier of the cell.” The current use of “intracellular protein” in the claims includes through example several transmembrane receptor proteins, such as EGFR (see claim 42), whereas such proteins do not fit the accepted definition of “intracellular protein” in the field of biochemistry. While the examiner interprets the claim to relate to the intracellular domains of the transmembrane proteins, such domains are not an intracellular protein on their own, so the full-length protein is not considered an intracellular protein. The term is indefinite because the specification does not clearly redefine the term. Furthermore, claims 2, 10, 11, 19, 35, 38, 75, 81, 88, 94, and 96 are rejected due to their dependence on the above listed claims. For the purpose of examination, the examiner will interpret “intracellular protein” to refer to fully intracellular proteins or the intracellular domain/region of a protein for which a portion of the protein can be found inside the membrane/wall of the cell.
Claim 9 recites the limitation “…wherein the targeting ligand covalently binds to an intracellular protein, wherein the intracellular protein is overexpressed compared to a corresponding wild-type protein…” This statement in unclear in meaning, especially with respect to the term “corresponding.” The statement “overexpressed compared to a corresponding wild-type protein” seems to include in its scope that the wild-type protein may be any protein in the cell, as it is unclear how the wild-type protein and the targeted protein are connected conceptually through the term “corresponding.” In view of the application as a whole, it appears this phrase could imply that the intracellular protein being targeted by the ligand is a mutant protein that is overexpressed compared to the corresponding wild-type form of itself (in the non-mutant state in other cells or beings). However, in its current form, the claim does not require the targeted protein to be a mutant protein. If “corresponding” is meant to describe the wild-type protein as being the wild-type form of the targeted protein, including non-mutant forms of the targeted protein in the scope of this limitation adds confusion, as it is not understood by the examiner how a wild-type target protein would be overexpressed relative to the wild-type version of itself. As it is unclear what the scope of this limitation is, the claim is thus considered indefinite and rejected under 35 U.S.C. § 112(b). Furthermore, claim 10 is rejected due to its dependence on claim 9. For the purpose of examination, the examiner will interpret this limitation to mean that the intracellular protein targeted by the targeting ligand is mutant and that the mutant targeted protein is overexpressed relative to the wild-type form of the same protein in otherwise comparative biological or analogous systems (cells, tissues, organisms).
Claim 108 recites the phrase “e.g.,” which is interpreted to be equivalent to the phrase “for example.” This phrase renders the claim indefinite because it is unclear whether the limitation following the phrase is part of the claimed invention. See MPEP § 2173.05(d). For the purpose of examination, the examiner will not interpret the phrase following “e.g.” to be required by the claim.
Claim Rejections - 35 USC § 112(d)
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 42 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 42 recites that the intracellular mutated protein may be EGFR, HER2, HER3, and FGFR (among several other options). Claim 42 depends from claim 1, requiring the mutated protein be an intracellular protein. However, the examiner notes that EGFR, HER2, HER3, and FGFR are known to be transmembrane receptor proteins. While these proteins contain intracellular domains, the protein on the whole is not considered an intracellular protein. Therefore, claim 42 fails to include all the limitations of the claim upon which it depends.
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.
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.
Claims 1-2, 11-12, 40, 42, 81, and 108 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Si (Si, Z.; et al., Cancer Biother. Radiopharm., 2019), as evidenced by Shien (Shien, K.; et al., Cancer Res., 2013).
Si teaches the synthesis of a molecule described as [99mTc]-complex13, which can be described as a conjugate of S-acetylmercaptoacetyltriglyglycinate and a quinazoline derivative bound to a radionuclide (pg. 551, Abstract; pg. 553, Fig. 1; and pg. 553-555, Synthesis of 12 and In vitro radiolabeling). Si describes that this molecule covalent binds to Cys773 of EGFR (pg. 552, left column, fourth paragraph), which is part of the intracellular cytoplasmic tyrosine kinase domain of EGFR (pg. 551, Introduction). Si demonstrates that this compound binds to EGFR in HCC 827 cells (pg. 555, Cellular uptake studies and Fig. 4).
Regarding claims 1 and 2, Si teaches the [99mTc]-complex13 conjugate (pg. 553, Fig. 1), which contains a targeting ligand, a linker, a metal chelator, and a radionuclide bound to the metal chelator. Si teaches that this molecule binds to EGFR covalently at Cys773 (pg. 552, left column, fourth paragraph), which is part of the intracellular cytoplasmic tyrosine kinase domain of EGFR (pg. 551, Introduction). Si also demonstrates that this compound binds to EGFR in HCC 827 cells (pg. 555, Cellular uptake studies and Fig. 4); which, as evidenced by Shien, are cells that contain mutant EGFR (exon 19 deletion) (pg. 3052, Cell lines and reagents). Therefore the [99mTc]-complex13 conjugate is understood by the examiner to contain a targeting ligand that covalently binds to the intracellular domain of a mutated EGFR protein.
Regarding claims 11 and 12, the [99mTc]-complex13 conjugate (pg. 553, Fig. 1) contains an electrophilic Michael acceptor group that binds to Cys773 (pg. 552, left column, fourth paragraph).
Regarding claims 40 and 42, Si teaches that the [99mTc]-complex13 conjugate targets EGFR, (pg. 552, left column, fourth paragraph), which is a protein overexpressed in various cancers and important to tumor progression (pg. 551, Introduction, first paragraph), making it a tumor-associated protein.
Regarding claim 81, the linker of the [99mTc]-complex13 conjugate (pg. 553, Fig. 1) covalently attaches the chelator to the targeting ligand.
Regarding claim 108, Si teaches that this molecule binds to EGFR covalently at Cys773 (pg. 552, left column, fourth paragraph) and teaches binding of the compound to EGFR through HCC 827 cell uptake (pg. 555, Cellular uptake studies and Fig. 4). As binding of the conjugate to EGFR results in the compound being covalently bound to the protein, such a reaction is understood to generate a covalently modified mutated EGFR comprising a cysteine residue linked to the conjugate.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 8, 9-12, 19, 35, 38, 40, 42, 75, 81, 94, and 108 are rejected under 35 U.S.C. 103 as being unpatentable over Planken (Planken, S.; et al., J. Med. Chem., 2017) in view of Si (Si, Z.; et al., Cancer Biother. Radiopharm., 2019).
Planken teaches several irreversible inhibitors of EGFR protein containing a T790M mutation (pg. 3002, Abstract). Planken teaches that these molecules bind to Cys797 of EGFR (pg. 3002, Introduction, first paragraph; pg. 3003, Figures 1 and 2; and pg. 3005, Figure 3). Planken teaches that compound 1 is a more potent inhibitor of mutant EGFR than WT EGFR (pg. 3003, Figure 1) and that this is also true for several other related derivatives (pg. 3004, Table 1; pg. 3008, Table 4; and pg. 3009, Table 5).
Planken does not teach a conjugate further comprising a metal chelator connected to a ligand via a linker.
As described above, Si teaches the synthesis of a molecule described as [99mTc]-complex13, which can be described as a conjugate of S-acetylmercaptoacetyltriglyglycinate and a quinazoline derivative bound to a radionuclide (pg. 551, Abstract; pg. 553, Fig. 1; and pg. 553-555, Synthesis of 12 and In vitro radiolabeling). Si describes that this molecule covalent binds to Cys773 of EGFR (pg. 552, left column, fourth paragraph), which is part of the intracellular cytoplasmic tyrosine kinase domain of EGFR (pg. 551, Introduction). Si demonstrates that this compound binds to EGFR in HCC 827 cells (pg. 555, Cellular uptake studies and Fig. 4). Si states that 99mTc can be used as a label for SPECT imaging (pg. 552, left column, third paragraph) and concludes that the [99mTc]-complex13 could feasibly be used as a SPECT probe (pg. 557, Conclusion).
A person of ordinary skill in the art would recognize that both Planken and Si disclose ligands that target the same protein (EGFR) that form covalent bonds with cysteines in the protein. It would also be recognized that Si teaches adding a chelated radionuclide to an already-known EGFR-targeting molecule to impart the new SPECT imaging property to the final structure.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the mutant EGFR-targeting ligand of Planken with the chelating group taught by Si because the EGFR targeting ligand of Planken is similar to the starting EGFR binding compounds of Si and they can be improved in the same way to add a chelating group, which enables radionuclide binding to impart properties such as SPECT imaging (MPEP § 2143(I)(C)). This would result in the predictable outcome of a conjugate comprising a mutant EGFR-targeting ligand, a chelator, and a linker.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Planken teaches several derivatives of the same EGFR targeting ligands with variable chemical groups attached that still maintain the inhibitory function, suggesting further modification at certain positions would not disrupt the inhibitory function of the molecules. Furthermore, the claims are silent regarding the structure of the linker, and medicinal chemists are capable of conjugating different chemical groups together by various means.
The skilled artisan would have been motivated to make this modification because it would enable the binding of various radionuclides, which can be used to impart various new properties on the molecules of Planken. This includes converting the molecules of SPECT imaging probes, enabling them to be used possibly for diagnostic purposes.
Regarding claims 1 and 2, Planken teaches several molecules that covalently bind to Cys797 of EGFR (Figures 1-4, 6, 8, and 10; and Tables 3, 4, 6, and 7). Planken describes the binding pocket as being in the kinase hinge region of EGFR (pg. 3003, Figure 1); and Si describes that the kinase domain of EGFR is an intracellular domain (pg. 551, Introduction). Therefore, the compounds of Planken are considered by the examiner to be targeting ligands that covalently bind to an intracellular protein. Planken further teaches that the disclosed compounds bind to mutated EGFR better than they bind to wild-type (WT, non-mutated) EGFR (Figures 1-2; and Tables 1, 2, and 4-7). Si teaches conjugating a chelating group to an EGFR-targeting ligand through an amide linking group (pg. 553, Fig. 1). Si further teaches binding a 99mTc radionuclide to the chelating group (pg. 553, Fig. 1b). Therefore, the combined teachings of Planken and Si render claims 1 and 2 obvious.
Regarding claim 8, Planken teaches that the disclosed compounds bind to Cys797 of mutated EGFR better than they bind to Cys797 in WT EGFR (Figures 1-2; and Tables 1, 2, and 4-7). Therefore, the combined teachings of Planken and Si render claim 8 obvious.
Regarding claim 9, Planken teaches several molecules that covalently bind to Cys797 of EGFR (Figures 1-4, 6, 8, and 10; and Tables 3, 4, 6, and 7). Planken describes the binding pocket as being in the kinase hinge region of EGFR (pg. 3003, Figure 1); and Si describes that the kinase domain of EGFR is an intracellular domain (pg. 551, Introduction). Therefore, the compounds of Planken are considered by the examiner to be targeting ligands that covalently bind to an intracellular protein. Planken further teaches that the disclosed compounds bind to mutated EGFR better than they bind to wild-type (WT, non-mutated) EGFR (Figures 1-2; and Tables 1, 2, and 4-7). Si teaches conjugating a chelating group to an EGFR-targeting ligand through an amide linking group (pg. 553, Fig. 1). As Planken teaches that the molecules covalently bind to Cys797 of EGFR (Figure 1), it is understood that the EGFR protein thus comprises one or more endogenous cysteine residues. Furthermore, Si describes that EGFR is known to be overexpressed in various cancers, including non-small-cell lung cancer (pg. 551, Introduction, first paragraph) and Planken describes that the T790M mutant in EGFR is a driver of non-small-cell lung cancer (pg. 3002, Introduction, first paragraph). Thus, in view of the aforementioned teachings of Si and Planken, the examiner interprets EGFR T790M to be a protein containing an intracellular domain that is mutated and is overexpressed in non-small-cell lung cancer compared to wild-type EGFR in healthy lung tissue. Therefore, the combined teachings of Planken and Si render claim 9 obvious.
Regarding claim 10, Si teaches binding a 99mTc radionuclide to the chelating group (pg. 553, Fig. 1b). Therefore, the combined teachings of Planken and Si render claim 10 obvious.
Regarding claims 11, 12, 19, 35, and 38, Planken teaches multiple EGFR-targeting ligands containing electrophilic groups (Figures 1-4, 6, 8, and 10; and Tables 3, 4, 6, and 7). Planken also teaches that this electrophilic group forms the covalent bond with the Cys797 residue of EGFR (Figures 1, 2, 4, and 6). Compound 1 (Figure 1) can be described as containing an electrophilic group as described in claim 19 wherein ring Q is a 5-membered heterocycloalkylene and E comprises Formula (Ic) wherein X is C(=O) and R5, R6, and R7 are all hydrogen. Compound 1 also can be considered to contain a group that can be described as the fourth electrophilic structural group provided in claim 35 wherein m is 1 and RQ is alkoxy. Compound 1 can be considered to contain the second to last electrophilic functional group listed in claim 38. Therefore, the combined teachings of Planken and Si render claims 11, 12, 19, 35, and 38 obvious.
Regarding claims 40 and 42, Planken teaches several molecules that covalently bind to Cys797 of EGFR (Figures 1-4, 6, 8, and 10; and Tables 3, 4, 6, and 7). Planken also states that the T790M mutant form of EGFR promotes cancer progression in non-small cell lung cancer (pg. 3002, Introduction). Additionally, Si teaches that EGFR is a protein overexpressed in various cancers and important to tumor progression (pg. 551, Introduction, first paragraph), making it a tumor-associated protein. Therefore, the combined teachings of Planken and Si render claims 40 and 42 obvious.
Regarding claim 75, Planken identified compound 21 (pg. 3002, Abstract Figure; and Table 7) as a clinical candidate resulting from the structure activity studies (pg. 3002, Abstract; and pg. 3016, Conclusion). Compound 21 is identical to the provided Mavelertinib structure in Table 1. Therefore, the combined teachings of Planken and Si render claim 75 obvious.
Regarding claim 81, Si teaches covalently attaching the chelating group to the EGFR targeting ligand through an amide linker (pg. 553, Fig. 1). Therefore, the combined teachings of Planken and Si render claim 81 obvious.
Regarding claim 94, Planken teaches solubilizing the EGFR targeting ligands in DMSO prior to adding the inhibitors to cell culture (pg. 3017, EGFR Cellular Autophosphorylation ELISA). DMSO is a pharmaceutically acceptable carrier. Thus, the preparations comprising the ligands and DMSO would be considered pharmaceutical compositions within the scope of this claim. Therefore, the combined teachings of Planken and Si render claim 94 obvious.
Regarding claim 108, Planken teaches several co-crystal structures of mutant EGFR proteins covalently modified in their intracellular domain by the EGFR-targeting ligands disclosed (Figures 1, 4, 6, and 8). Therefore, the combined teachings of Planken and Si render claim 108 obvious.
Claims 1-2, 4, 11-12, 19, 35, 38, 40, 42, 81, 94, 96, and 108 are rejected under 35 U.S.C. 103 as being unpatentable over Blake (US 10,689,377 B2 – provided by applicant in IDS filed May 6, 2024) in view of Si (Si, Z.; et al., Cancer Biother. Radiopharm., 2019).
Blake teaches irreversible inhibitors of KRAS G12C (column 1, lines 5-9). Such compounds have the core structure of formula (I) (column 10, lines 42-55) and may be further modified by many structures disclosed throughout the specification. Embodiments of the KRAS G12C inhibitors of Blake include those disclosed in columns 19-128. Blake describes the inhibitors irreversibly bind to KRAS G12C by forming a covalent adduct with the sulfhydryl side chain of the cysteine residue at position 12 (column 7, lines 18-27). Blake describes that the G12C notation denotes that the KRAS protein is a mutant form in which glycine has been substituted to cysteine as a result of the mutation (column 7, lines 11-16). Blake further teaches that these inhibitors may be provided as pharmaceutical compositions (column 205, line 25 through column 206, line 21). Blake also teaches that these inhibitors or the compositions comprising these inhibitors may be used for the treatment of cancer (column 207, lines 1-7).
Blake does not teach a conjugate further comprising a metal chelator connected to a ligand via a linker.
As described above, Si teaches the synthesis of a molecule described as [99mTc]-complex13, which can be described as a conjugate of S-acetylmercaptoacetyltriglyglycinate and a quinazoline derivative bound to a radionuclide (pg. 551, Abstract; pg. 553, Fig. 1; and pg. 553-555, Synthesis of 12 and In vitro radiolabeling). Si describes that this molecule covalent binds to Cys773 of EGFR (pg. 552, left column, fourth paragraph), which is part of the intracellular cytoplasmic tyrosine kinase domain of EGFR (pg. 551, Introduction). Si demonstrates that this compound binds to EGFR in HCC 827 cells (pg. 555, Cellular uptake studies and Fig. 4). Si states that 99mTc can be used as a label for SPECT imaging (pg. 552, left column, third paragraph) and concludes that the [99mTc]-complex13 could feasibly be used as a SPECT probe (pg. 557, Conclusion).
A person of ordinary skill in the art would recognize that both Blake and Si disclose ligands that target an intracellular protein (KRAS) or an intracellular domain of a protein (EGFR). It would also be recognized that Si teaches adding a chelated radionuclide to such a targeting ligand imparts a new SPECT imaging property to the molecule.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the mutant KRAS-targeting ligand of Blake with the chelating group and radionuclide taught by Si because the KRAS targeting ligand of Blake is similar to the starting compound of Si (in that they are both irreversible inhibitors of intracellular protein (domains)) and they can be improved in the same way to impart the SPECT imaging property (MPEP § 2143(I)(C)). This would result in the predictable outcome of a conjugate comprising a mutant KRAS-targeting ligand, a chelator, and a linker.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Blake teaches several derivatives of the same KRAS G12C targeting ligands with variable chemical groups attached that still maintain the inhibitory function, suggesting further modification at certain positions would not disrupt the inhibitory function of the molecules. Furthermore, the claims are silent regarding the structure of the linker, and medicinal chemists are capable of conjugating different chemical groups together by various means.
The skilled artisan would have been motivated to make this modification because it would impart a new property (SPECT imaging probe) on the molecules of Blake, enabling them to be used possibly for diagnostic/theranostic purposes.
Regarding claims 1 and 2, Blake teaches several molecules that covalently bind to Cys12 of KRAS G12C, an intracellular protein (columns 19-128). Blake teaches that the ligands bind to the G12C form of KRAS, which is a mutation (column 7, lines 11-16). Additionally, Si teaches conjugating a chelating group to a protein-targeting ligand through an amide linking group (pg. 553, Fig. 1). Si further teaches binding a 99mTc radionuclide to the chelating group (pg. 553, Fig. 1b). Therefore, the combined teachings of Blake and Si render claims 1 and 2 obvious.
Regarding claim 4, Blake describes that the G12C notation denotes that the KRAS protein is a mutant form in which glycine has been substituted to cysteine as a result of the mutation (column 7, lines 11-16). The examiner interprets this to mean that the mutant KRAS comprises a mutant-specific cysteine residue that is absent in the corresponding WT sequence of the KRAS protein. Therefore, the combined teachings of Blake and Si render claim 4 obvious.
Regarding claims 11, 12, 19, 35, and 38, Blake teaches multiple KRAS G12C targeting ligands containing electrophilic groups that bind to the mutant cysteine residue (columns 19-128). These structures contain many electrophilic groups that read on these claims. As an example, the first structure in column 19 contains an electrophilic group that reads on claim 19 wherein ring Q is a 6-membered heterocycloalkane and E comprises formula (Ic) wherein X is C(=O) and R5, R6, and R7 are all hydrogen; the fourth structure of claim 35 wherein m is 1 and RQ is alkoxy; and the second to last electrophilic functional group listed in claim 38. Therefore, the combined teachings of Blake and Si render claims 11, 12, 19, 35, and 38 obvious.
Regarding claims 40 and 42, Blake teaches several molecules that covalently bind to Cys12 of KRAS G12C (columns 19-128). Blake describes that KRAS has a role in malignancy and is mutated in multiple tumor types (column 1, lines 21-45). The examiner interprets this to mean that KRAS is a tumor-associated protein. Therefore, the combined teachings of Blake and Si render claims 40 and 42 obvious.
Regarding claim 81, Si teaches covalently attaching the chelating group to the EGFR targeting ligand through an amide linker (pg. 553, Fig. 1). Therefore, the combined teachings of Blake and Si render claim 81 obvious.
Regarding claim 94, Blake teaches that these inhibitors may be provided as pharmaceutical compositions (column 205, line 25 through column 206, line 21). Such pharmaceutical compositions may include a pharmaceutically acceptable carrier or excipient (column 205, lines 26-30). Therefore, the combined teachings of Blake and Si render claim 94 obvious.
Regarding claim 96, Blake teaches that these inhibitors or the compositions comprising these inhibitors may be used for the treatment of cancer (column 207, lines 1-7). Such a method includes administering to a patient a therapeutically effective amount of one of the inhibitors. Therefore, the combined teachings of Blake and Si render claim 96 obvious.
Regarding claim 108, Blake teaches that the inhibitors irreversibly bind to KRAS G12C by forming a covalent adduct with the sulfhydryl side chain of the cysteine residue at position 12 (column 7, lines 18-27). Blake also teaches a KRAS G12C modification assay wherein exemplary compounds are incubated with KRAS G12C and covalent adducts of the protein and ligand are detected by LCMS (column 1639, line 35 through column 1640, line 26). Detection of any signal for the adduct would indicate the presence of a covalently modified protein comprising an intracellular protein comprising a cysteine residue and a targeting ligand. The combination with Si, as described above, would result in a protein covalently modified by a conjugate that reads on that of claim 1. Therefore, the combined teachings of Blake and Si render claim 108 obvious.
Claim 88 is rejected under 35 U.S.C. 103 as being unpatentable over Planken in view of Si, as applied to claims 1-2, 8, 11-12, 19, 35, 38, 40, 42, 75, 81, 94, and 108 above, and further in view of Dawicki (Dawicki, W.; et al., Oncoimmunology, 2019).
As described above, Planken teaches several irreversible inhibitors of EGFR protein containing a T790M mutation (pg. 3002, Abstract). Planken teaches that these molecules bind to Cys797 of EGFR (pg. 3002, Introduction, first paragraph; pg. 3003, Figures 1 and 2; and pg. 3005, Figure 3). Additionally, Si teaches the synthesis of a molecule described as [99mTc]-complex13, which can be described as a conjugate of S-acetylmercaptoacetyltriglyglycinate and a quinazoline derivative bound to a radionuclide (pg. 551, Abstract; pg. 553, Fig. 1; and pg. 553-555, Synthesis of 12 and In vitro radiolabeling). Si describes that this molecule covalent binds to Cys773 of EGFR (pg. 552, left column, fourth paragraph), which is part of the intracellular cytoplasmic tyrosine kinase domain of EGFR (pg. 551, Introduction). Si demonstrates that the conjugate of the chelating group and the EGFR targeting molecule enables the binding of the radionuclide 99mTc (pg. 553, Fig. 1b), which enables the molecule to be used for SPECT imaging (pg. 552, left column, third paragraph; and pg. 557, Conclusion). As described above, the combination of Planken in view of Si results in the EGFR-targeting molecules of Planken being conjugated to a chelating group.
The combination of Planken and Si does not teach a conjugate comprising the radionuclide actinium-225.
Dawicki teaches an actinium-225 containing conjugate of Daratumumab (pg. 1, Abstract). Daratumumab is a CD38-targeting antibody used in the treatment of cancers (pg. 1, Introduction). CD38 has been used as a means for targeting tumors (pg. 1-2, Introduction), suggesting that CD38 is a tumor-associated protein. Dawicki teaches covalent conjugation of a DOTA derivative chelator to the antibody through a linker and binding of the actinium-225 radionuclide to the chelator (pg. 2, Figure 1; and pg. 7, Materials and methods, second and third paragraphs). Dawicki discloses that alpha-emitters such as actinium-225 have advantages for use in radiotherapeutics, as such radionuclides possess high linear energy transfer and demonstrate good cancer cell killing efficiency (pg. 2, left column, second paragraph). Dawicki further describes that conjugation of an alpha particle emitter like actinium-225 to a tumor-targeting molecule like an antibody increases the antitumor potency of the antibody (pg. 2, left column, second paragraph; and pg. 3, Figure 3).
A person of ordinary skill in the art would recognize that both the molecules of the combination of Planken and Si and the actinium-225 radioimmunoconjugate of Dawicki are molecules containing a portion of the molecule that specifically targets proteins associated with cancers, a linker, and a chelating group. A person of ordinary skill in the art would recognize that the chelating group taught by Si can bind various radiometals, not just 99mTc, including 225Ac. It would be recognized that combining 225Ac with an anti-cancer inhibitor molecule can lead to increased antitumor effects.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the molecules of the combination of Planken and Si containing a mutant EGFR-targeting ligand, a linker, and a chelator with the coordinating of the actinium-225 radionuclide taught by Dawicki because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a mutant EGFR-targeting molecule conjugated to a chelator containing 225Ac.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because the chelating groups of Si and Dawicki are polyamines that are capable of binding various radionuclides (especially radiometals) and methods of coordinating such radionuclides to the chelating groups are demonstrated by both Si and Dawicki.
The skilled artisan would have been motivated to make this modification because it would combine a targeted cancer therapeutic with an alpha-emitting radionuclide, imparting improved cell-killing properties associated with alpha-emitting radiotherapeutics, as discussed by Dawicki.
Regarding claim 88, as described above, the combination of Planken and Si teach a molecule that renders claim 1 obvious. Planken teaches several molecules that covalently bind to Cys797 of EGFR (Figures 1-4, 6, 8, and 10; and Tables 3, 4, 6, and 7). Si teaches conjugating a chelating group to an EGFR-targeting ligand through an amide linking group (pg. 553, Fig. 1). Additionally, Dawicki teaches coordination of actinium-225 in a chelating group linked to an antibody that targets a tumor-associated protein (CD38) (pg. 2, Figure 1). Therefore, the combined teachings of Planken, Si, and Dawicki render claim 88 obvious.
Claims 1, 2, 11 69, 81, and 108 are rejected under 35 U.S.C. 103 as being unpatentable over Sanches (Sanches, M.; et al., Nat. Commun., 2014) in view of Si (Si, Z.; et al., Cancer Biother. Radiopharm., 2019).
Sanches teaches the mechanism of action of multiple IRE1 inhibitors (pg. 1, Abstract). Among these inhibitors is MKC9989 (pg. 3, Figure 1a), which Sanches demonstrates through a co-crystal structure covalently binds to Lys907 of IRE1α, forming a Schiff base (pg. 6, figure 3). Through structure-activity relationship studies, Sanches demonstrates that MKC9989 inhibits the F889A mutant of IRE1α in an in-vitro RNase activity assay (pg. 7, Figure 4d).
Sanches does not teach a conjugate further comprising a metal chelator connected to a protein-targeting ligand via a linker.
As described above, Si teaches the synthesis of a molecule described as [99mTc]-complex13, which can be described as a conjugate of S-acetylmercaptoacetyltriglyglycinate and a quinazoline derivative bound to a radionuclide (pg. 551, Abstract; pg. 553, Fig. 1; and pg. 553-555, Synthesis of 12 and In vitro radiolabeling). Si describes that this molecule covalent binds to Cys773 of EGFR (pg. 552, left column, fourth paragraph), which is part of the intracellular cytoplasmic tyrosine kinase domain of EGFR (pg. 551, Introduction). Si demonstrates that this compound binds to EGFR in HCC 827 cells (pg. 555, Cellular uptake studies and Fig. 4). Si states that 99mTc can be used as a label for SPECT imaging (pg. 552, left column, third paragraph) and concludes that the [99mTc]-complex13 could feasibly be used as a SPECT probe (pg. 557, Conclusion).
A person of ordinary skill in the art would recognize that both Sanches and Si disclose protein-targeting ligands that target intracellular proteins and form covalent bonds with them. It would also be recognized that Si teaches adding a chelated radionuclide to such a targeting ligand imparts a new SPECT imaging property to the molecule.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the IRE1α-targeting ligand of Sanches with the chelating group taught by Si because the IRE1α targeting ligand of Sanches is similar to the EGFR binding compound of Si (in that they covalently modify a target protein) and they can be improved in the same way to add a chelating group, which enables radionuclide binding to impart properties such as SPECT imaging (MPEP § 2143(I)(C)). This would result in the predictable outcome of a conjugate comprising am IRE1α-targeting ligand, a chelator, and a linker.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Sanches teaches multiple IRE1α inhibitors possessing the same core structure and aldehyde with various other attached chemical groups, suggesting some modifications can be made to the core structure while maintaining inhibitory function. Furthermore, the claims are silent regarding the structure of the linker, and medicinal chemists are capable of conjugating different chemical groups together by various means.
The skilled artisan would have been motivated to make this modification because it would enable the binding of various radionuclides, which can be used to impart various new properties on the molecules of Sanches. This includes converting the molecules of SPECT imaging probes, enabling them to be used possibly for diagnostic or theranostic purposes.
Regarding claim 1, Sanches teaches several molecules that target and covalently bind to Lys907 of IRE1α (pg. 3, Figure 1a; and pg. 6, Figure 3). Sanches describes IRE1 proteins as ER transmembrane proteins (pg. 2, left column, third paragraph), which makes them intracellular proteins. Additionally, Sanches teaches that MKC9989 inhibits the F889A mutant form of IRE1α (pg. 7, Figure 4d), indicating that MKC9989 covalently binds to a mutated intracellular protein. Additionally, Si teaches conjugating a chelating group to a protein-targeting ligand through an amide linking group (pg. 553, Fig. 1). Therefore, the combined teachings of Sanches and Si render claim 1 obvious.
Regarding claim 2, Si further teaches binding a 99mTc radionuclide to the chelating group (pg. 553, Fig. 1b). Therefore, the combined teachings of Sanches and Si render claim 2 obvious.
Regarding claim 11, the compounds of Sanches (pg. 3, Figure 1a) contain aldehydes, which are electrophilic groups. Therefore, the combined teachings of Sanches and Si render claim 11 obvious.
Regarding claim 69, Sanches teaches that MKC9989 forms a covalent bond with Lys907 of IRE1α (pg. 3, Figure 3) and demonstrates that the inhibitor activity is similar between the WT and F889A mutant forms of IRE1α (pg. 7, Figure 4d), indicating covalent inhibition of the mutated intracellular protein. Therefore, the combined teachings of Sanches and Si render claim 69 obvious.
Regarding claim 81, Si teaches covalently attaching the chelating group to the protein targeting ligand through an amide linker (pg. 553, Fig. 1). Therefore, the combined teachings of Sanches and Si render claim 81 obvious.
Regarding claim 108, Sanches teach a co-crystal structure of IRE1α covalently modified by MKC9989 (pg. 6, Figure 3). Additionally, Sanches demonstrates that the inhibitor activity is similar between the WT and F889A mutant forms of IRE1α (pg. 7, Figure 4d), indicating the formation of a covalent adduct of the mutated intracellular protein and MKC9989. Therefore, the combined teachings of Sanches and Si render claim 108 obvious.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claim 1 is provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claim 1 of copending Application No. 18/431,656 (reference application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 4, 11, 19, 35, 38, 42, 94, and 96 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 18, 22, 24, 43-45, 47, 71, and 74 of copending Application No. 18/431,646 (reference application) in view of Si (Si, Z.; et al., Cancer Biother. Radiopharm., 2019).
The claims of copending Application No. 18/431,646 are drawn to a radiopharmaceutical conjugate comprising a targeting ligand that covalently binds to an intracellular KRAS protein wherein the intracellular KRAS protein is mutated and wherein the conjugate comprises a linker and radionuclide. The claims depending from claim 1 of the 18/431,646 application specify that the radionuclide is an isotope of iodine.
The claims of copending Application No. 18/431,646 do not include a metal chelating group and a bound radiometal.
As described above, Si teaches the synthesis of a molecule described as [99mTc]-complex13, which can be described as a conjugate of S-acetylmercaptoacetyltriglyglycinate and a quinazoline derivative bound to a radionuclide (pg. 551, Abstract; pg. 553, Fig. 1; and pg. 553-555, Synthesis of 12 and In vitro radiolabeling). Si describes that this molecule covalent binds to Cys773 of EGFR (pg. 552, left column, fourth paragraph), which is part of the intracellular cytoplasmic tyrosine kinase domain of EGFR (pg. 551, Introduction). Si demonstrates that this compound binds to EGFR in HCC 827 cells (pg. 555, Cellular uptake studies and Fig. 4). Si states that 99mTc can be used as a label for SPECT imaging (pg. 552, left column, third paragraph) and concludes that the [99mTc]-complex13 could feasibly be used as a SPECT probe (pg. 557, Conclusion).
A person of ordinary skill in the art would recognize that both the copending Application No. 18/431,646 and Si disclose ligands that target and covalently bind an intracellular protein (KRAS) or an intracellular domain of a protein (EGFR). It would also be recognized that Si teaches adding a chelated radionuclide to such a targeting ligand imparts a new SPECT imaging property to the molecule.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the mutant KRAS-targeting ligand of copending application 18/431,646 by substituting the radioiodine with the chelating group and radiometal taught by Si because these features serve the same purpose (MPEP § 2143(I)(B)). This would result in the predictable outcome of a conjugate comprising a mutant KRAS-targeting ligand, a chelator, and a linker.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because these groups serve similar functions and medicinal chemists are capable of conjugating different chemical groups together by various means.
The skilled artisan would have been motivated to make this modification because it would provide an alternative means of radiolabeling the compound, allowing for the storage of the compound in the form of the empty chelator and addition of the radiometal immediately before use. That way, synthesis of the entire molecule close in proximity to the time of utilization would not be required.
Regarding instant claim 1, conflicting claim 1 of copending application 18/431,646 (henceforth to be referred to as the copending ‘646 application) is drawn to a conjugate comprising a targeting ligand that binds to an intracellular KRAS protein wherein the intracellular KRAS protein is mutated. Additionally, Si teaches conjugating a chelating group to a protein-targeting ligand through an amide linking group (pg. 553, Fig. 1). Si further teaches binding a 99mTc radionuclide to the chelating group (pg. 553, Fig. 1b).
Regarding instant claim 2, Si further teaches binding a 99mTc radionuclide to the chelating group (pg. 553, Fig. 1b).
Regarding instant claim 4, conflicting claim 24 of the copending ‘646 application is drawn to a conjugate targeting KRAS G12C. The examiner interprets this notation to mean that the wild-type sequence has a Gly at the 12th position and this mutant has a Cys at the 12th position instead. Thus, this mutant comprises one or more mutant-specific cysteine residues absent in a corresponding wild-type sequence.
Regarding instant claims 11, 19, 35, and 38, the structures of conflicting claim 22 of the copending ‘646 application contain these electrophilic functional groups.
Regarding instant claim 42, conflicting claim 1 of the copending ‘646 application is drawn to a conjugate wherein the intracellular protein is KRAS.
Regarding instant claim 94, conflicting claim 71 of the copending ‘646 application is drawn to a pharmaceutical composition comprising a radiolabeled conjugate of conflicting claim 1 and a pharmaceutically acceptable excipient or carrier.
Regarding instant claim 96, conflicting claim 74 of the copending ‘646 application is drawn to a method of treating cancer in a subject in need thereof comprising administering to the subject a radiolabeled conjugate of conflicting claim 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
Prosecution Insights