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
The present Application, filed November 10, 2023, is a Continuation of International Patent Application No. PCT/US2022/028755, filed May 11, 2022, which claims priority to U.S. Provisional Patent Application No. 63/187,041, filed May 11, 2021, respectively.
Status of the Claims
In the amendment filed June 28, 2024, claims 3-7, 9-16, 18, 20, 25-37, 39-43, 46, 48-56, 58, 62-76, 78-82, and 87-89 are canceled. Claims 2, 8, 17, 19, 21-24, 38, 44-45, 47, 57, 59-61, 77, and 84-86 are amended. Claims 1-2, 8, 17, 19, 21-24, 38, 44-45, 47, 57, 59-61, 77, and 83-86 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on August 13, 2025 is acknowledged.
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 38, 47, and 77 are indefinite:
Claims 38, 47, and 77 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.
In particular, each of these claims, depending directly or indirectly from claim 1, recites a narrowed Markush group for several variable chemical moieties, and then recites even more narrowed Markush groups for the same variables, describing the narrower groups as being preferable. For example, claim 38 recites the compound of claim 1, limited to the narrower Formula (IV), but “optionally” limited to the narrower still Formula V, and still “preferably” limited to one of the even narrower Formulae (VI-1) through (VII-4). Somewhat similarly, claims 47 and 77 recite a Markush group of alternatives for moiety R14, but preferably a narrower group. Description of examples or preferences in this manner should be set forth in the specification rather than the claims because, when recited in the claims, examples and preferences create confusion over the intended claim scope. See MPEP § 2173.05(d) and cases cited therein.
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 1-2, 8, 17, 19, 21-24, 45, 47, 57, 59, and 84-86 fail to comply with the written description requirement:
Claims 1-2, 8, 17, 19, 21-24, 45, 47, 57, 59, and 84-86 are rejected under 35 U.S.C. § 112, 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 inventors, at the time the application was filed, had possession of the claimed invention.
Specifically, Applicant does not have written description support for the full breadth of the compound genera recited in claims 1-2, 8, 17, 19, 21-24, 45, 47, 57, 59, nor for the pharmaceutical compositions containing these compounds or the methods of treatment using them. As discussed further below, the working examples of the instant specification cover only a small fraction of the chemical space covered by the claimed genera. Furthermore, the art indicates that, variations in regions such as linkers in macrocylized kinase inhibitors can have large effects on activity. As such, the present claims directed to extremely large chemical genera lack sufficient written description.
The written description requirement is distinct from the enablement requirement; as was first pointed out by the court in In re Ruschig, 3 79 F .2d 990, 154 USPQ 118 (CCP A 1967), and clarified in Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 19 USPQ2d 1111 (Fed. Cir. 1991). The issue of whether the claimed subject matter is adequately supported/described by the specification, is a question of fact. Id. at 1563, 19 USPQ2d at 1116.
When considering whether the claimed subject matter complies with the written description requirement, Applicants' disclosure should be read in light of the knowledge possessed by those skilled in the art.
"[T]he disclosure in question must be read in light of the knowledge possessed by those skilled in the art, and that knowledge can be established by affidavits of fact composed by an expert, and by referencing to patents and publications available to the public ... "
In re Lange, 644 F.2d 856, 863, 209 USPQ 288, 294. See also, In re Alton, 76 F.3d 1168, 37 USPQ2d 1578 (Fed. Cir. 1996).
Applicants enjoy the presumption that their patent application is valid and all statements contained therein are accurate; it is the PTO's burden to demonstrate why any of Applicants claims should be rejected or why any of Applicant's statements should be doubted.
"it is incumbent upon the Patent Office, whenever a rejection ... is made, to explain why it doubts the truth or accuracy of any statement in a supporting disclosure and to back up assertions of its own with acceptable evidence or reasoning which is inconsistent with the contested statement. Otherwise, there would be no need for the applicant to go to the trouble and expense of supporting his presumptively accurate disclosure."
In re Marzocchi, 439 F.2d 220, 224, 169 USPQ 367, 370. If successful in presenting such evidence and argument, the burden then shifts to the Applicant to provide evidence that would convince one to the contrary.
The Invention in General
A component of Applicant’s invention is directed to crystal forms of a compound of formula (I)
PNG
media_image1.png
198
208
media_image1.png
Greyscale
where the variable groups are as defined. For example, ring C can be heteroaryl and ring B can be heteroaryl or one of several alternative ring types. The compounds of formula (I) are described as inhibitors of epidermal growth factor receptor (EGFR), including mutant forms of EGFR. EGFR is a receptor tyrosine kinase that is mutated in a number of cancers, and it is thought that EGFR inhibitors can be useful in treating certain cancers, particularly cancers having mutant EGFR, when the inhibitor is effective toward the mutant variant.
The Claimed Invention
The claimed invention is directed to the compounds of formula I (shown above) where the variable moieties are as defined. The variable moieties are defined very broadly in claim 1, such that the genus conservatively contains well over 1020 individual compounds. For example, considering only the X3-L1-X4 portion of the macrocycle linker with two linker termini, L1 has nine different categories of moieties, and each of X3 and X4 have seven categories. Thus this linker with termini has 441 alternatives just at the category level. When further considering that most categories of moieties have a multitude of individual possibilities, ranging from dozens (e.g. C1-6 alkylene) to hundreds or thousands (e.g. 3- to 10-membered heterocyclene, for L1) themselves have hundreds to thousands of individual possibilities themselves, the number of possibilities for the linker alone is very conservatively in the tens of thousands, more plausibly upwards of a million. Similarly, rings B and C conservatively have several hundred permutations each, while the available substitutions (R1, R2, R3) containing nested substitutions, increases the number of alternatives by many orders of magnitude.
Claims 2, 8, 17, 19, 21-24, 45 each slightly narrow the broad genus of claim 1, each generally limiting the options for one variable group. Claim 38 narrows the genus considerably more, specifying exact moieties for rings A and B and substituent R3, as well as the linker termini, X3 and X4, and limits L1 to two alternatives. Claim 44, depending from claim 38, limit the genus still further.
Claim 47 slightly narrows the broad genus of claim 1, in a manner that is unclear (see the rejection for indefiniteness), and claims 57 and 59-60, depending from claim 47, slightly narrow the genus further. Claim 61, 77, and 83 put appreciable limits on the breadth of the genus of claimed compounds.
Claim 84 is directed to a pharmaceutical composition having any compound of claim 1, while claims 85-86 recite methods of treating cancer, involving administering to a human any compound of claim 1.
The Supporting Disclosure
The Detailed Description of Applicant’s supporting disclosure provides a number of definitions (pgs. 21-38, and then describes the chemical genera (e.g. formula I) in terms substantially the same as those of claims 1-2 as well as progressively narrower chemical formulae such as the formula VIII recited in claim 61 (pgs. 39-68). The supporting disclosure further lists a variety of exemplary narrower Markush groups for various variable moieties as particular embodiments (pgs. 69-91) and lists 169 working examples, actual compounds of formula I that were synthesized, along with their experimental mass spectrometry data (Table A, pgs. 92-119), and notes that the compounds of Formula I, in at least some embodiments, can be reversible EGFR inhibitors.
Of note, all of compounds 1-169 occupy a narrow swathe of the structural landscape of formula (I). For example, all have X3 and X4 as O and L1 as C4 alkylene (isobutyl).
Applicant’s disclosure then describes general methods of synthesizing the disclosed compounds, appearing to be fairly specific to the working examples, compounds 1-169 (pgs. 119-124), and describes various options for and embodiments of pharmaceutical compositions containing the disclosed compounds (pgs. 125-130). The disclosure briefly describes kits having compounds of the disclosure, and methods for treating cancer involving administration of compounds of the disclosure, and describes properties such as selective inhibition of EGFR that may be observed with certain disclosed compounds (pgs. 131-147).
The disclosure further provides specific examples of compound synthesis (Compound 169, 48, 28, 25, 58, 96, 105, 151, 127 - pgs. 148-185).
PNG
media_image2.png
139
221
media_image2.png
Greyscale
PNG
media_image3.png
152
202
media_image3.png
Greyscale
PNG
media_image4.png
169
381
media_image4.png
Greyscale
PNG
media_image5.png
117
191
media_image5.png
Greyscale
PNG
media_image6.png
147
148
media_image6.png
Greyscale
Finally, the disclosure describes in vitro assays testing the inhibitory activity of select compounds toward EGFR kinase and various mutants thereof, as well as anti-proliferation activity toward Ba-F3 cells (pgs. 186-188).
The State of the Art
A number of references establish that the compounds of instant formula I are macrocyclic versions of known, linear (nonmacrycyclic) EGFR inhibitors, cyclized according to a known structural approach of connecting opposite ends of the inhibitor via a linear linker. Furthermore, a number of these references establish that variations in optional substituents and in the linker itself can substantially impact biological activity of the macrocyclic molecule created via this approach.
For example, Linker Modification Enables Control of Key Functional Group Orientation in Macrocycles, J. Med. Chem., 68, pgs. 24890-24923 (2025) to Brudy et al. (hereinafter, “Brudy”) states that:
As purely synthetic macrocycles are frequently derived from nonmacrocyclic compounds, the following nomenclature is often used when discussing the macrocycles: The chemical moiety of the macrocycle, which can be found without (or only with minor) modifications in the nonmacrocyclic parent compound, is referred to as the core, while the moiety that connects two (or more) parts of the aforementioned core, and thereby forms the macrocyclic ring, is called a linker.
-Brudy, pg. 24890, right column, first full paragraph
Furthermore, U.S. Patent No. 9,890,152 to Bryan et al. teaches inhibitors of the T790M mutant of EGFR (Abstract) having a Formula (I)
PNG
media_image7.png
118
241
media_image7.png
Greyscale
such as compound 251, (6-(2-(3-Amino-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-1-isopropyl-1H-imidazo[4,5-c]pyridin-2-yl)methanol
PNG
media_image8.png
107
306
media_image8.png
Greyscale
which encompasses the three-ring portion of instant formula I, where pyrimidine ring corresponds to instant ring C, the pyrazole ring corresponds to instant ring B with substituents R3, and the imidazole moiety, minus the isopropyl and methanol substituents, corresponds to instant R2.
The compounds of instant claim 1 can thus be understood substantially as macrocyclized EGFR inhibitors, formed connecting linker portions, instant L1, via termini X3 and X4, to opposite ends of substantially known linear EGFR inhibitors. This structure corresponds to the macrocyclic structure of a core (known EGFR inhibitor) cyclized by a linker, as taught by Brudy.
Brudy, an investigation of the effects of linker modifications on macrocyclized FGBP51 ligands as a model system, teaches that minor modifications to a macrocyclic scaffold influence conformational preorganization, and that the presence of absence of a single methyl group in the linker region can have a ten-fold effect on binding affinity (Abstract).
Similarly, the non-patent publication, Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors, ChemMedChem, 12, pgs. 207-213 (2017) by McIver et al. (hereinafter, “McIver”) teaches a structure-based design and optimization of Mer tyrosine kinase inhibitors (Abstract). McIver teaches that simple changes in linker length, by altering the number of methylene groups, can create multi-order of magnitude differences in IC50 toward the target kinase (Table 1).
To improve the MerTK activity of compound 2, we initially explored the ring size of the macrocycle, as this would simultaneously vary the position of the hydrogen bond donor, the amino group, and the flexibility of the ring. As shown in Table 1, when m=1, the inhibitory activity of macrocycles varied depending on the ring size. Compound 2 (n=2) was 3-fold more potent than compound 3 (n=1), however, compound 4 (n=3) was 12-fold less active than compound 2. When n≥4, the potency of the macrocycles was improved as the macrocyclic ring size was increased (compounds 4–7). The trend was also evident when m=2. Compound 8 (n=1) was a weak MerTK inhibitor with micromolar potency while compound 11 (UNC2541) (n=4) was very potent with a low nanomolar IC50 against MerTK. The MerTK inhibitory activities of compound 9 (n=2) and 10 (n=3) were intermediate. When the macrocyclic ring became larger (n=5 or 6), the MerTK activity of the corresponding analogues 12 and 13 was retained…
-McIver, pg. 209, left column
McIver further teaches that changes in the functional group within the linker can have large impacts on macrocyclic inhibitor activity.
we varied the linker of the macrocycle to explore if any other linker would improve the cellular activity (Table 3). When the primary amine was protected by a Boc group (26) or removed (27), the activity against MerTK was dramatically reduced…In addition, replacement of the amide group in 11 with a less polar ester group such as in 29, preserved activity in either the MerTK MCE or pMerTK ELISAs. Another attempt to decrease the polarity while retaining the hydrogen bond donor property of the α-amino amide linker was to replace it with a secondary hydroxy group. Three analogues were prepared (30–32). The ring size and the position of the hydrogen bond donor of analogue 30 was the same as analogue 10. Both analogues had similar MerTK activity; however, the Flt3 selectivity of 30 was diminished from 89-fold (10) to 24-fold (30). The activity and selectivity were worse for analogue 31. Although the ring size and the position of the hydrogen donor of 31 was the same as 12, analogue 31 was 34-fold less active than 12 in the MerTK MCE assay and only had 5-fold selectivity over Flt3…Linkers containing oxygen as the hydrogen bond acceptor such as epoxide (33) or ether (34 and 35), showed much lower MerTK inhibitory activity. More rigid macrocycles containing a phenyl ring resulted in analogues 36 and 37. Analogue 36 had the same-sized macrocycle with its hydrogen bond acceptor, an amino group, at the same position as 22. However, it was 27-fold less active than 22 in the MCE assay. Similarly, analogue 37 was 7-fold weaker than 25 with similar selectivity over Flt3. Overall, the amide linker was optimal in this series.
-McIver, pg. 209, right column
In short, the art indicates that even small changes in the linker of a macrocyclic ligand/inhibitor can have large effects on efficacy, and thus indicates that, where structural space within the genus of instant Formula (I) is untested for efficacy, efficacy cannot reasonably be assumed.
Summary of Written Description Rejection
In summary, compound claim 1 is directed to a very large genus of macrocyclic compounds (difficult to calculate with precision, but likely greater than 1020); meanwhile 169 real examples of compounds of claim 1 are reported. Furthermore, these real examples fail to exemplify the full structural scope encompassed by the genus of claim 1. This is particularly true in the linker region, where all 169 real examples have substantially the same linker structure. This sampling of species actually produced fails to properly support the vast scope of the genus of claim 1. Claims 2, 8, 17, 19, 21-24, 45, 47, 57, and 59, depending from claim 1, reduce the breadth of this genus somewhat, but not enough to be supported by the limited supportive breadth of the real examples.
Composition and method claims 84-86, depending from claim 1, are insufficiently supported for the same reasons. In addition, method claims 85-86 implicitly depend upon an EGFR-inhibiting or other therapeutic activity that is not satisfactorily supported by the instant disclosure. In particular, the functional results of the instant specification are derived only from the structurally limited pool of real examples 1-169, while the art shows that variations in linkers can have large effects on functional efficacy of macrocyclic compounds. As such, it is not clear that the genus of compounds of claim 1 would have the requisite activity to effectively mediate the claimed methods of treatment.
For the aforementioned reasons, claims 1-2, 8, 17, 19, 21-24, 45, 47, 57, 59, and 84-86 fail to satisfy the written description requirement.
Allowable Subject Matter
Claims 44, 60-61, and 83 are 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.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629