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 instant application, filed 07/18/2023, is a national stage entry of PCT/CN2021/141767, filed 12/27/2021, which claims foreign priority to CN202110203074.5 and CN202110203701.5, filed 02/23/2021, and CN202110152506.4, filed 02/03/2021.
Amendments and Claim Status
The amendment filed on 03/18/2026 is acknowledged and entered.
Claims 6-8 are amended;
Claims 1-9 are pending and are under prosecution.
Information Disclosure Statement
The Information Disclosure Statement filed on 07/18/2023 is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the information disclosure statement is considered.
Restriction/Election
Applicant’s election without traverse of Group I in the reply filed on 03/18/2026 is acknowledged. Furthermore, the election of the following species is acknowledged: Species A compound of Formula (I) (CAS RN: 2819685-03-3); Species B: lenalidomide; Species C: lymphoma; Species D: human.
Claims 1-9 are pending in the instant application. Claims 3, 4, 9 are withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species. Therefore, claims 1, 2, 5-8 read on an elected invention and species and are therefore under consideration in the instant application.
In accordance with the MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reexamined. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
Figure 1. Elected Species
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Figure 1. (S)-4-(1-acryloylpiperidin-3-yl)-6-(4-phenoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-7- carboxamide, CAS RN 2819685-03-3
As per MPEP § 803.02, the Examiner will determine whether the entire scope of the claims is patentable. Applicants' elected species (Figure 1) makes a contribution over the prior art of record. Thus, according to MPEP § 803.02: should the elected species appear allowable, the search of the Markush-type claim will be extended. The Markush-type claim shall be rejected and claims to the nonelected invention held withdrawn from further consideration. It has been determined that the entire scope claimed is not patentable.
Status of Claims
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Upon examination, the elected species is determined to be allowable based on the present record. In view of the allowability of the elected species, and in accordance with MPEP § 803.02, the search of the Markush-type claim has been extended to include a single nonelected species. In view of the non-elected species, claim 4 is rejoined as it reads on a non-elected species, CAS Registry Number: RN 1643568-13-1, shown on the right. [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 1643568-13-1, Entered STN: 04 Jun 2015]. All claims drawn to nonelected species remain withdrawn from consideration. As such, claims 1, 4, 6-8 read on the nonelected species, to which the Markush-type claim has been extended, and are therefore under consideration in the instant application, and being examined on the merits as such.
Specification
The disclosure is objected to because of the following informalities:
Throughout the specification, the spelling of “membered” referring to a number of members in a ring system is misspelled as “memebered.”
Further regarding the specification, the limitations L1, L2 and U are defined as being selected “from bond.” However, this does not follow proper English grammar rules, and should instead read “from a bond.”
Further regarding the specification, L1 is defined as possibly being —C0alkyl—. However, this limitation can be confusing, and should be replaced with “a bond,” so as not to confuse a person of ordinary skill in the art.
Further regarding the specification, on page 2, line [0012], the following definition is put forth:
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The definition of the parent ring moiety with N in the position of X
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is inconsistent with the definition of the ring moieties which follow, which have X in said position of N.
Appropriate correction is required.
Claim Objections
Claims 1, 4, and 5 are objected to for the following informalities:
Throughout claims 1 and 4 the spelling of “membered” referring to a number of members in a ring system is misspelled as “memebered.”
Further regarding claim 1, R is defined as being selected from
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this should be rewritten including commas between the individual possible substituents as “
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, H, or D”
Further regarding claim 1, L1 and L2 are defined as possibly being —C0-4alkyl—. However, the limitation C0alkyl can be confusing, and should be replaced with “a bond, —C1-4alkyl—, ” etc. so as to be consistent with the limitations of L1 and L2 as recited in claim 2: “bond, —C1-4alkyl—".
Further regarding claims 1 and 2, the limitations L1, L2 and U are defined as being selected “from bond.” However, this does not follow proper English grammar rules, and should instead read “from a bond.”
Regarding claim 5, a comma should be used to separate “the pharmaceutically acceptable salt, or the stereoisomer thereof.” Presently, there is no comma separating “the salt or the stereoisomer.”
Appropriate correction is required.
Claim Interpretation
The instant claims are subject to the following interpretation:
Claim 1 recites N in the position of X in the ring moiety definitions.
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In applying the broadest reasonable interpretation of the claims set forth in MPEP § 2111, the claim is interpreted as having X in the position of N in the core ring
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in order to be consistent with the ring definitions which follow.
Claim Rejections - 35 U.S.C. § 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, 4, and 6-8 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 claim 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 1, 2, 4, and 6-8 of the instant application are drawn to compounds having following substituents:
R is independently selected from
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, H or D;
L1 is independently selected from —C0-4alkyl-, —CR1R2—, —C1-2alkyl(R1)(OH)—, —C(O)—, —CR1R2O—, —OCR1R2—, —SCR1R2—, —CR1R2S—, —NR1—, —NR1C(O)—, —C(O)NR1—, —NR1C(O)NR2—, —CF2—, —O—, —S—, —S(O)m—, —NR1S(O)2—, —S(O)2NR1—;
L2 is independently selected from —C0-4alkyl-, —CR1R2—, —C1-2alkyl(R1)(OH)—, —C(O)—, —CR1R2O—, —OCR1R2—, —SCR1R2—, —CR1R2S—, —NR1—, —NR1C(O)—, —C(O)NR1—, —NR1C(O)NR2—, —CF2—, —O—, —S—, —S(O)m—, —NR1S(O)2—, —S(O)2NR1—;
Ar1 and Ar2 are independently selected from phenyl, 5-6 membered heteroaryl, and the phenyl and the 5-6 membered heteroaryl are optionally substituted with one or more G1;
X is independently selected from N, CR3;
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is independently selected from the structure below:
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n is 1 or 2;
U is independently selected from bond, —C1, 2, 5-8alkyl-, —CR4R5—, —C1-2alkyl(R4)(OH)—, —C(O)—, —CR4R5O—, —OCR4R5—, —SCR4R5—, —CR4R5S—, —NR4—, —NR4C(O)—, —C(O)NR4—, —NR4C(O)NR5—, —CF2—, —O—, —S—, —S(O)m—, —NR4S(O)2—, —S(O)2NR4—;
Y is absent or selected from C3-8cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered bicycloalkyl, 5-12 membered heterobicycloalkyl, 5-12 membered spirocycloalkyl, 5-12 membered heterospirocycloalkyl, aryl or heteroaryl, and the C3-8cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered bicycloalkyl, 5-12 membered heterobicycloalkyl, 5-12 membered spirocycloalkyl, 5-12 membered heterospirocycloalkyl, aryl and heteroaryl are optionally substituted with one or more G3;
Z is independently selected from CN, —NR12CN
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;
when a is a double bond, Ra, Rb, and Rc are independently selected from H, D, —CN, halogen, C1-6alkyl, C3-6cycloalkyl or C3-6heterocycloalkyl, and the C1-6alkyl, C3-6cycloalkyl and C3-6heterocycloalkyl are optionally substituted with one or more G4;
when a is a triple bond Rb is H, D, —CN, halogen, C1-6alkyl, C3-6cycloalkyl or 3-6 heterocycloalkyl, and the C1-6alkyl, C3-6cycloalkyl and 3-6 heterocycloalkyl are optionally substituted with one or more G5;
R12 is independently selected from H, D, C1-6alkyl, C3-6cycloalkyl or C3-6heterocycloalkyl, and C1-6alkyl, C3-6cycloalkyl and C3-6heterocycloalkyl are optionally substituted with one or more G6;
G1, G2, G3, G4, G5, and G6 are each independently selected from H, D, —CN, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or 3-8 heterocycloalkyl, C6-10 membered aryl, 5-10 membered heteroaryl, —OR6, —OC(O)NR6R7, —C(O)OR6, —C(O)NR6R7, —C(O)R6, —NR6R7, —NR6C(O)R7, —NR6C(O)NR7R8, —S(O)mR6 or —NR6S(O)mR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, 3-8 heterocycloalkyl, C6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with the substituent of one or more CNs, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or 3-8 heterocycloalkyl, C6-10 membered aryl, 5-10 membered heteroaryl, —OR9, —OC(O)NR9R10, —C(O)OR9, —C(O)NR9R10, —C(O)R9, —NR9R10, —NR9C(O)R10, —NR9C(O)NR10R11, —S(O)mR9 or —NR9S(O)iR10;
R3, R4, R5, R6, R7, R8, R9, R10 and R11 are each independently selected from H, D, —CN, halogen, C1-6alkyl-, C3-8cycloalkyl or 3-8 heterocycloalkyl, aryl or heteroaryl;
m is 1 or 2
35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the "specification shall contain a written description of the invention ...." This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc); Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111,1114 (Fed. Cir. 1991); see also Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004) (discussing the history and purpose of the written description requirement); In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim’s enablement is not equally conclusive of that claim’s satisfactory written description"). The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert, denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Bees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); EliLilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm.,927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). An application specification may show actual reduction to practice by describing testing of the claimed invention.
In the present case, the important factors leading to a conclusion of inadequate written description is the absence of any working example of the invention as claimed, and the lack of predictability in the art.
In the instant specification, there is no disclosure of compounds having the following claimed substituents:
R as D;
L1 as —C1, 2, 5-8alkyl-, —CR1R2—, —C1-2alkyl(R1)(OH)—, —C(O)—, —CR1R2O—, —OCR1R2—, —SCR1R2—, —CR1R2S—, —NR1—, —NR1C(O)—, —C(O)NR1—, —NR1C(O)NR2—, —CF2—, —O—, —S—, —S(O)m—, —NR1S(O)2—, —S(O)2NR1;
L2 as —C0-4alkyl-, —CR1R2—, —C1-2alkyl(R1)(OH)—, —C(O)—, —CR1R2O—, —OCR1R2—, —SCR1R2—, —CR1R2S—, —NR1—, —NR1C(O)—, —C(O)NR1—, —NR1C(O)NR2—, —CF2—, —S—, —S(O)m—, —NR1S(O)2—, —S(O)2NR1—;
Ar1 and Ar2 as 5-6 membered heteroaryl, and the phenyl and the 5-6 membered heteroaryl are optionally substituted with one or more G1;
X as CR3;
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as
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n as 2;
U as —C1, 2, 5-8alkyl-, —CR4R5—, —C1-2alkyl(R4)(OH)—, —C(O)—, —CR4R5O—, —OCR4R5—, —SCR4R5—, —CR4R5S—, —NR4—, —NR4C(O)—, —C(O)NR4—, —NR4C(O)NR5—, —CF2—, —O—, —S—, —S(O)m—, —NR4S(O)2—, —S(O)2NR4;
Y as C3-8cycloalkyl, 3-4 or 7-8 membered heterocycloalkyl, 5-12 membered bicycloalkyl, 5-12 membered heterobicycloalkyl, 5-12 membered spirocycloalkyl, 5-12 membered heterospirocycloalkyl, aryl or heteroaryl, and the C3-8cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered bicycloalkyl, 5-12 membered heterobicycloalkyl, 5-12 membered spirocycloalkyl, 5-12 membered heterospirocycloalkyl, aryl and heteroaryl are optionally substituted with one or more G3;
Z as CN, —NR12CN,
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when a is a double bond Ra as D, —CN, halogen, C1-6alkyl, C3-6cycloalkyl or C3-6heterocycloalkyl, and the C1-6alkyl, C3-6cycloalkyl and C3-6heterocycloalkyl are optionally substituted with one or more G4
when a is a double bond Rb as D, —CN, halogen, C1-6alkyl, C3-6cycloalkyl or C3-6heterocycloalkyl, and the C1-6alkyl, C3-6cycloalkyl and C3-6heterocycloalkyl are optionally substituted with one or more G4
when a is a double bond Rc as D, —CN, halogen, C1-6alkyl, C3-6cycloalkyl or C3-6heterocycloalkyl, and the C1-6alkyl, C3-6cycloalkyl and C3-6heterocycloalkyl are optionally substituted with one or more G4;
when a is a triple bond Rb as H, D, —CN, halogen, C2-6alkyl, C3-6cycloalkyl or 3-6 heterocycloalkyl, and the C1-6alkyl, C3-6cycloalkyl and 3-6 heterocycloalkyl are optionally substituted with one or more G5;
R12 as H, D, C1-6alkyl, C3-6cycloalkyl or C3-6heterocycloalkyl, and C1-6alkyl, C3-6cycloalkyl and C3-6heterocycloalkyl are optionally substituted with one or more G6;
G1 and G3 as D, —CN, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or 3-8 heterocycloalkyl, C6-10 membered aryl, 5-10 membered heteroaryl, —OR6, —OC(O)NR6R7, —C(O)OR6, —C(O)NR6R7, —C(O)R6, —NR6R7, —NR6C(O)R7, —NR6C(O)NR7R8, —S(O)mR6 or —NR6S(O)mR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, 3-8 heterocycloalkyl, C6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with the substituent of one or more CNs, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or 3-8 heterocycloalkyl, C6-10 membered aryl, 5-10 membered heteroaryl, —OR9, —OC(O)NR9R10, —C(O)OR9, —C(O)NR9R10, —C(O)R9, —NR9R10, —NR9C(O)R10, —NR9C(O)NR10R11, —S(O)mR9 or —NR9S(O)iR10; G1 and G3 are H
G2, as D, —CN, halogen, C2-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or 3-8 heterocycloalkyl, C6-10 membered aryl, 5-10 membered heteroaryl, —OR6, —OC(O)NR6R7, —C(O)OR6, —C(O)NR6R7, —C(O)R6, —NR6R7, —NR6C(O)R7, —NR6C(O)NR7R8, —S(O)mR6 or —NR6S(O)mR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, 3-8 heterocycloalkyl, C6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with the substituent of one or more CNs, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or 3-8 heterocycloalkyl, C6-10 membered aryl, 5-10 membered heteroaryl, —OR9, —OC(O)NR9R10, —C(O)OR9, —C(O)NR9R10, —C(O)R9, —NR9R10, —NR9C(O)R10, —NR9C(O)NR10R11, —S(O)mR9 or —NR9S(O)iR10; G2 is H and C1alkyl,
G4, G5, and G6 H, D, —CN, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or 3-8 heterocycloalkyl, C6-10 membered aryl, 5-10 membered heteroaryl, —OR6, —OC(O)NR6R7, —C(O)OR6, —C(O)NR6R7, —C(O)R6, —NR6R7, —NR6C(O)R7, —NR6C(O)NR7R8, —S(O)mR6 or —NR6S(O)mR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, 3-8 heterocycloalkyl, C6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with the substituent of one or more CNs, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or 3-8 heterocycloalkyl, C6-10 membered aryl, 5-10 membered heteroaryl, —OR9, —OC(O)NR9R10, —C(O)OR9, —C(O)NR9R10, —C(O)R9, —NR9R10, —NR9C(O)R10, —NR9C(O)NR10R11, —S(O)mR9 or —NR9S(O)iR10; G4, G5, and G6 are not exemplified.
R3, R4, R5, R6, R7, R8, R9, R10 and R11 as H D, —CN, halogen, C1-6alkyl-, C3-8cycloalkyl or 3-8 heterocycloalkyl, aryl or heteroaryl;
m as 2;
The instant specification (pages 25-58) teaches compounds which are characterized as having only the following substituents:
R is
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and H
L1 is —C0—
L2 is —O—,
Ar1 and Ar2 are phenyl
X is N
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is
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n is 1
is a bond
Y is 5-6 membered heterocycloalkyl
Z is
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when a is a double bond Ra is H
when a is a double bond Rb is H
when a is a double bond Rc is H
when a is a triple bond Rb is C1alkyl
R12 is not exemplified
G1 and G3 are H
G2 is H and C1alkyl,
G4, G5, and G6 are not exemplified.
R3, R4, R5, R6, R7, R8, R9, R10 and R11 are not exemplified.
Therefore, the compounds described in the instant specification detail only a limited number of the total substituents claimed (see substituents 1-16, above). All working examples presented in the instant specification are related to the compounds containing a fraction of the total claimed substituents (see substituents 37-54, above).
There are no working examples in the instant specification for the wide range of substituents claimed, but for which evidence of possession has not been provided (see substituents 17-36, above). Thus the instant specification does not provide any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application.
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F. 3d 1565, 1572, 41 USPQ2d 1961, 1966(1997); In re Gosteli, 872 F.2d 1008, 1012,10 USPQ2d 1614, 1618 (Fed Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.") Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For example, disclosure of only a method of making the invention and the function may not be sufficient to support a product claim other than a product-by-process claim. See, e.g., Fiers v. Revel, 984 F.2d at 1169, 25 USPQ2d at 1605; Amgen, 927 F.2d at 1206, 18 USPQ2d at 1021.
Thus, since Applicant has not described in adequate detail methods to synthesize compounds containing the claimed substituents, or provided evidence that said compounds have been characterized, or that they exist, an ordinary skilled artisan could not completely envisage Applicants’ invention. Moreover, it is clear that the written description requirement has not been met since Applicant has not provided any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application. Thus, claims 1, 4, and 6-8 of the instant application are not supported by the instant specification and thus a rejection under 35 U.S.C. § 112 (a) for failing to comply with the written description requirement is proper.
Claim 7 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 a compound of Formula (I) for use in the inhibition of BTK, it does not reasonably provide enablement for a compound of Formula (I) for use in the prevention of lymphoma or any other disease related to the excessive activity of BTK. The specification does not provide sufficient information to support the claim as recited.
The instant specification fails to provide information that would allow the skilled artisan to fully practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors, which are considered in determining whether undue experimentation is required to practice the invention:
(1) Nature of the invention;
(2) Breadth of the claims;
(3) State of prior art;
(4) Level of ordinary skill in the art;
(5) Level of predictability in the art;
(6) Amount of direction provided;
(7) Presence of working examples; and
(8) Quantity of experimentation required to make or use the invention.
In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
All of the Wands factors have been considered with regard to the instant claim, with the most relevant factors discussed below.
Nature of the invention: Claim 7 of the instant application is drawn to a compound for use in the prevention and/or treatment of diseases and/or symptoms related to the excessive activity of BTK, elected to be lymphoma.
Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. Applicant claims that the claimed compounds can be used to treat a subject having, suspected of having, or at risk of developing diseases and/or symptoms related to the excessive activity of BTK. Thus the cited claims are deemed very broad since these claims read on essentially preventing any disease and/or any symptoms related to the excessive activity of BTK comprising the administration of a compound of Formula (I), which includes subjects at risk of developing a broad range of cancers.
State of the Prior Art: While the state of the art with regard to the treatment of lymphoma and other cancer is relatively high, the state of the art with regard to the prevention of lymphoma and other cancers is underdeveloped. This is because there would be no way to determine that lymphoma or other cancers would have predictably occurred without treatment.
Regarding prevention of cancer, the American Cancer Society maintains that “There's no sure way to prevent cancer, but you can help reduce your risk by making healthy choices like eating right, staying active, and not smoking” (American Cancer Society. Cancer Risk and Prevention).
Regarding prevention of lymphoma, Winship Cancer Institute maintains that lymphoma may be prevented by behaviors which “(limit) the risk of contracting infections and making lifestyle changes that help maintain a healthy immune system” (Winship Cancer Institute, Lymphoma prevention).
Predictability/Unpredictability in the Art: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity in preventing diseases. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that the recitation encompasses the prevention of cancer and other disorders and treating subjects and risk of developing and those subjects suspected of having disorders related to the excessive activity of Bruton Tyrosine Kinase. Thus, the skilled artisan would view that the prevention of all disorders/diseases encompassed by the claims, by administering a compound of Formula (I), is highly unpredictable.
Guidance of the Specification/Working Examples: Applicant has only provided working examples suggesting that compounds of Formula (I) may degrade BTK in vitro (pages 58-61). Thus, the specification fails to provide sufficient evidence in support of prevention or treatment of those suspected of having or at risk of developing diseases and/or symptoms related to the excessive activity of BTK as recited in the instant claims.
Additionally, the examples provided do not demonstrate the prevention of any disease or symptom related to the excessive activity of BTK. The disclosure does not discuss, or demonstrate through working examples, a method that could be used to determine that recurrence of diseases or symptoms were prevented using the claimed agents as there is no disclosed method to determine that recurrence of any of the aforementioned diseases would have predictably occurred without treatment.
The Quantitation of Experimentation Required: In order to practice Applicants invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to demonstrate that the claimed compounds could be administered to a subject at risk of developing diseases and/or symptoms related to the excessive activity of BTK. The population of subjects could include any subject, and thus the quantitation of experimentation is unreasonably large. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome.
In conclusion, Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”. The prevention of diseases or symptoms related to the excessive activity of Bruton Tyrosine Kinase is not enabled by the instant specification.
Claim 7 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 a compound of Formula (I) for use in the inhibition of BTK it does not reasonably provide enablement for a compound of Formula (I) for use in the treatment of lymphoma or any other disease related to the excessive activity of BTK. The specification does not provide sufficient information to support the claim as recited.
The instant specification fails to provide information that would allow the skilled artisan to fully practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors, which are considered in determining whether undue experimentation is required to practice the invention:
(1) Nature of the invention;
(2) Breadth of the claims;
(3) State of prior art;
(4) Level of ordinary skill in the art;
(5) Level of predictability in the art;
(6) Amount of direction provided;
(7) Presence of working examples; and
(8) Quantity of experimentation required to make or use the invention.
In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
All of the Wands factors have been considered with regard to the instant claim, with the most relevant factors discussed below.
Nature of the invention: Claim 7 of the instant application is drawn to a compound for use in the prevention and/or treatment of the diseases and/or symptoms related to the excessive activity of BTK, elected to be lymphoma.
Breadth of the claim: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. Applicant claims that the claimed compounds can be used to treat any disease and/or any symptoms related to the excessive activity of BTK. Thus the cited claims are deemed very broad since these claims read on treating all the diseases and/or symptoms related to the excessive activity of BTK, which includes numerous diseases and symptoms.
State of the Prior Art: There are no art recognized methods that could be used to establish that the instantly claimed diseases can be commonly addressed using the claimed therapeutic intended use of the compounds claimed. Additionally, the disclosure does not discuss, or demonstrate through working examples, a method using the claimed agents. Additionally, there are no art recognized methods that could be used to identify subjects who would have predictably developed the broad spectrum of the cancers claimed in order to determine that the cancers were treated using the claimed compounds.
Regarding common disease mechanisms and biomarkers in cancer, McKean et al. (Biomarkers in precision cancer immunotherapy: Promise and challenges. American Society of Clinical Oncology – Educational Book (2020), 40, p.e275-e291), hereinafter McKean, teaches that although ongoing studies and trials investigate the use of multiple biomarkers predictive of patient response or harm, none of these are comprehensive in predicting potential benefit (of treatment). This unmet need for validated biomarkers is largely secondary to a prohibitive complexity within tumor parenchyma and tumor microenvironment, dynamic clonal and proteomic changes to therapy, heterogenous host immune defects, and varied standardization among sample preparation and reporting (Abstract). McKean also teaches that treatment failures occur even in ICI patient cohorts, despite respective prescreening with biomarkers such as PD-L1 tumor proportion scores (p.e275). Regarding gene expression profiles specifically, McKean teaches that an important concept within gene expression profiles is that the predictive utility of such algorithms may be dependent on individual therapy plans. Data suggest that signaling and transcriptomic patterns may correlate only with response to therapy of directly related targets (p.e280). Unrelated immune pathways may require separate and individualized gene expression assays for different therapies (p.e280). Therefore, the selection of a particular therapy for any specific type of cancer is unpredictable, and requires individualized assays that are fully described to achieve correlation.
Predictability/Unpredictability in the Art: The pharmaceutical arts, particularly the treatment of cancer, are well-recognized as highly unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. The courts have upheld that in unpredictable arts, a greater degree of specificity is required to satisfy the enablement requirement. Cancer comprises a heterogeneous group diseases the distinct molecular drivers, signaling pathways, and therapeutic responses. As such, a person of ordinary skill in the art would recognize the inhibition of cancer- implicated enzymes in vitro, do not reliably predict therapeutic efficacy across different cancers, cancer subtypes, or patient populations. The translation of enzyme inhibition or cell line activity into effective cancer treatment depends on numerous factors, including tumor biology, compensatory signaling mechanisms, tissue specific effects, toxicity, and therapeutic window, none of which are addressed in a comprehensive or predictive manner in the instant specification.
Moreover, one of skill in the art would recognize that it is highly unpredictable in regard to therapeutic effects, side effects and toxicity generated by administering a singular class of compounds for treating all the diseases and cancers encompassed by the claims.
Guidance of the Specification/Working Examples: Applicant has only provided working examples suggesting that compounds of claim 1 may inhibit BTK in vitro (pages 58-61). Thus, the specification fails to provide sufficient evidence in support of the broad treatment of all diseases and/or symptoms related to the excessive activity of BTK as recited in the instant claims.
The Quantitation of Experimentation Required: In order to practice Applicants invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to demonstrate that the large range of diseases and/or symptoms related to the excessive activity of BTK can be treated by the administration of the compounds claimed. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome. Such experimentation would necessarily include cancer specific validation of therapeutic efficacy, optimization of dosing regimens, assessment of toxicity and side effect profiles, and identification of responsive versus nonresponsive cancer subtypes. The specification provides only limited in vitro data demonstrating activity in to the numerous additional cancers recited in the claims. Accordingly, determining which cancers may be effectively treated would require extensive, individualized experimentation, amounting to undue burden.
In conclusion, Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”. A compound of Formula (I) useful in treating all diseases and/or symptoms related to the excessive activity of BTK is not enabled by the instant specification.
Claim Rejections - 35 U.S.C. § 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, 4, and 6-8 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.
Regarding claim 1, the claim 1 recites N in the position of X in the parent ring definition
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, but later uses X in the same position when defining the different moieties.
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It is unclear whether or not applicant intended for N to be X, or if X should be interpreted as N in all instances, rendering the claim indefinite.
Regarding claims 6-8, the claims recite the limitation "prodrugs thereof according to claim 1.” There is insufficient antecedent basis for this limitation in the claims, because a prodrug is not recited in claim 1.
Further regarding claims 6-8, the claims are deemed to be indefinite for being in an improper format. It’s unclear if the claims are intended to be product claims or are intended to be method claims. Product claims do not encompass administration or preparation steps as claimed in dependent claims 7 and 8.
Further regarding claims 7 and 8 of the instant application, the claim recite a compound useful for preventing and/or treating diseases and/or symptoms related to the excessive activity of BTK comprising administering to a compound or pharmaceutically acceptable salt thereof of Formula (I).
It is unclear what “related to the excessive activity of BTK” refers to and how to determine if a disease is related to the excessive activity of BTK. The term “related to the excessive activity of BTK” in claims 7 and 8 is a relative term which renders the claim indefinite. The term “related to the excessive activity of BTK” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification does not define how to determine if a disease is related to the excessive activity of BTK. Thus it is unclear what would be considered related to the excessive activity of BTK by a person of ordinary skill in the art. There are a large number of diseases and/or symptoms that could be considered related to the excessive activity of BTK. Moreover, there are diseases and/or symptoms that could result from BTK dysfunction that do not directly have BTK at the center of the disease and/or symptom morphology. The claims, as written, do not distinctly claim the disease and/or symptom to which BTK is related, nor how the relation is made—whether it be a disease, condition, or disorder directly implicating BTK dysfunction or a disease which develop as a result of diseases, conditions, or disorders that implicate BTK dysfunction directly. Thus an ordinary skilled artisan cannot ascertain the metes and bounds of the claimed invention and thus the claims are properly rejected as being indefinite.
Regarding claim 4, the claim depends on a claim rejected as indefinite (claim 1) and does not remedy the indefiniteness of the claim. As such, claim 4 is dually rejected as indefinite.
Claim Rejections - 35 U.S.C. § 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, 4, 7, and 8 are rejected under 35 U.S.C. § 102(a)(1) and 35 U.S.C. § 102(a)(2) as being anticipated by Bounafoux et al. (WO 2014210255 A1, published December 31, 2014, cited on applicant IDS dated 07/18/2023), hereinafter Bounafoux.
The instant claims are drawn to a compound of Formula (I) useful in preventing and/or treating diseases and/or symptoms related to the excessive activity of BTK, elected in the instant case to be lymphoma.
Bounafoux teaches carboxamide compounds, pharmaceutically acceptable salts, and prodrugs useful for treating lymphoma (Abstract, see instant claim 7). Specifically, Bounafoux teaches 4-(2-methyl-3-(2-methylenebutanamido)phenyl)-1H-indole-7-carboxamide (claim 20, line 26, page 359, see instant claims 1 and 4), also known as CAS Registry Number: RN 1643568-13-1. [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 1643568-13-1, Entered STN: 04 Jun 2015] (see Figure 2). Bounafoux further teaches the determination of proper dosages in humans (pages 47 and 48, see instant claim 8), as well as processing of the active compounds in preparations which can be used pharmaceutically (page 44). Bounafoux teaches the compound is capable of 50-90% inhibition of BTK (page 48, see instant claim 8). The compound taught by Bounafoux anticipates a compound of Formula (I) according to Figure 2, wherein,
Figure 2. Structural comparison of instantly claimed Formula (I) and prior art compound
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Fig 2. a) instantly claimed Formula (I); b) CAS Registry Number: RN 1643568-13-1
X is CR3 and R3 is H
R is H
U is a bond
Y is 6-memberd aryl substituted with G3, wherein G3 is CH3
Z is
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, wherein a is a double bond, Ra is CH2CH3 and Rb and Rc are H
The teachings set forth above are herein applied to each claim individually and the claims stand rejected.
Claim Rejections - 35 U.S.C. § 103
The following is a quotation of pre-AIA 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.
Claim 6 is rejected under 35 U.S.C. § 103 as being unpatentable over Bounafoux (see earlier citation), as applied to claims 1, 4, 7, and 8, above, and further in view of Dobrovolsky et al (Blood, Volume 133, Issue 9, pages 952–961, published February 28, 2019), hereinafter Dobrovolsky.
The instant claims are drawn to a compound of Formula (I) useful in preventing and/or treating diseases and/or symptoms related to the excessive activity of BTK. The instant claims are further drawn to a compound of Formula (I) and pharmaceutical compositions thereof in combination with a second therapeutic agent elected to be lenalidomide.
Bounafoux is as set forth above.
Bounafoux fails to disclose lenalidomide as the elected second therapeutic agent in combination with a compound of Formula (I).
The deficiencies of Bounafoux are remedied by Dobrovolsky, who discloses wherein lenalidomide is undergoing late-stage clinical trials for use in treatment of a number of lymphomas (page 953), and implicates BTK inhibition as a target strategy for treating those lymphomas (page 952).
A person of ordinary skill in the art, prior to the filing date of the instant claims, would have been motivated to combine lenalidomide with a compound of Formula (I) because both agents are directed to a common purpose, i.e., treating lymphoma associated with BTK dysfunction. Bounafoux explicitly teaches combination therapies of a compound of Formula (I) with chemotherapeutic agents (page 32), directing a person of ordinary skill in the art towards this combination. According to MPEP 2144.06 (I), combining equivalents known for the same purpose is rendered obvious. The courts have said,
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.).
Therefore, combining a compound of Formula (I) with lenalidomide as taught by Bounafoux and Dobrovolsky respectively, to treat lymphoma implicating BTK dysfunction would have been prima facie obvious to a person of ordinary skill in the art.
Correspondence
Claims 1, 4, and 5 are objected to.
Claims 1, 2, 4 and 6-8 are rejected.
Claims 3 and 9 are withdrawn.
No claim is allowed.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
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