DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1, 3-21, and 27 are pending. Claims 2 and 22-26 are cancelled.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/US2022/034247, filed on June 21, 2022. This application also claims priority to U.S. Provisional Application No. 63/213,386, filed on June 22, 2021.
Specification - Abstract
The abstract of the disclosure is objected to because it is not in compliance with 37 C.F.R. 1.72 (b). Specifically, the sheet presenting the abstract includes other parts of the application or other material. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The inclusion of formula (I) in the abstract is appropriate and may be retained in the revised abstract.
Specification - Disclosure
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1, 3, 4, 8, and 19 are objected to because of the following informalities:
In claim 1:
“each R1 is independently… OH,, NRaRb…” should read“each R1 is independently… OH, NRaRb…” [i.e., the extra comma after “OH” should be removed”
For consistency, in claims 3 and 4:
“optionally substituted with OH” should read“optionally substituted with one to three OH”
For consistency, in claim 8:
“cyclobutanyl” should read “cyclobutyl”
In claim 19:
“bicycle[1.1.1]pentanyl” should read “bicyclo[1.1.1]pentanyl”
Appropriate correction is required.
As there are a number of objections identified, Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the claim set.
Examiner’s note on novelty and nonobviousness
The closest prior art is:
Schalm et al. (Schalm) (Schalm, S. S. et al. 1296P BLU-945, a highly potent and selective 4th generation EGFR TKI for the treatment of EGFR T790M/C797S resistant NSCLC. Annals of Oncology 2020, 31, S839.; published September 2020).
Novelty:
Schalm teaches the compound, BLU-945, (which has the following formula according to STN):
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as a highly potent and selective 4th generation EGFR TKI for the treatment of EGFR T790M/C797S resistant non-small cell lung cancer (NSCLC). BLU-945 (with the exception of the region indicated by the dashed circle) comprises structural elements encompassed by the corresponding structural regions of instant Formula (I). The main structural distinction between BLU-945 and instant Formula (I) resides in the circled region. Specifically, BLU-945 requires the substituent in that position to be a heterocyclyl instead of a heteroaryl group as required by instant Formula (I). Since there is no complete structural overlap between BLU-945 and the instant compounds, the instant invention is considered novel.
Nonobviousness:
Both Schalm and the present invention disclose EGFR inhibitors. Although a POSITA would have been motivated to further explore derivatives of the compounds disclosed in Schalm (such as the compounds of the present invention) as EGFR inhibitors, Schalm does not teach nor suggest modifying ring-A of BLU-945 with specifically a heteroaryl, cycloalkyl, or cycloalkenyl group to arrive at compounds encompassed by instant Formula (I).
Thus, the instant invention is considered nonobvious.
Claim Rejections - 35 USC § 112(a) – Scope of enablement
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, 3-21, and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A compound of Formula (I)
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or a pharmaceutically acceptable salt thereof, wherein:
Z is O
A1, A2, and A3 are as recited in claim 1
Ring A is as recited in claim 1
Each R1 is independently halogen, OH, C1-C4 alkyl, or C1-C4 alkoxy, wherein the alkyl represented by R1 or in the group represented by R1 is optionally substituted with 1 to 3 groups selected from halogen, OH, and C1-C2 alkyl; and/or two R1, when attached to the same carbon atom, form =O, or together with the carbon atom to which they are both attached form a 4 to 6-membered heterocyclyl
n is as recited in claim 1
R2 is C1-C4 alkyl, wherein the alkyl represented by R2 is optionally substituted with 1 to 3 groups selected from halogen and OH
R3 and R4 is as recited in claim 1
R5 and R6 is H or unsubstituted C1-C4 alkyl
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims a compound represented by structural formula (I):
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or a pharmaceutically acceptable salt thereof useful for treating a cancer. The variables of formula (I) are defined in instant claim 1.
State of the prior art
See “Examiner’s note on novelty and nonobviousness” section above which discusses the teachings of Schalm.
Further, Schalm also evaluated BLU-945’s in vivo anti-tumor activity in an NCI-H1975 cell line (i.e., non-small cell lung cancer cell line)-derived tumor xenograft (CDX) model as well as in osimertinib-resistant CDX- and patient-derived xenograft (PDX) models of NSCLC (see “Methods” section). Schalm discloses that oral administration of BLU-945 to tumor-bearing mice demonstrated potent EGFR pathway inhibition and anti-tumor activity at well-tolerated doses in the subcutaneous NCI-H1975 CDX model and osimertinib-resistant CDX and PDX models, as well as in the intracranial luc-H1975 model of NSCLC (see “Results” section, last sentence).
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry and organic synthesis and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The presence or absence of working examples; the amount of direction or guidance present; and quantity of experimentation necessary
According to MPEP § 2163:
“Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’ See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
In the instant case, even though the specification provides data on the inhibitory effects (evaluated in biochemical and cellular assays) of compounds of diverse structures (see biological examples 1 and 2 of instant specification), it does not include any data on the inhibitory effects of compounds of instant Formula (I) with structural elements that are outside the scope of the enabling elements listed above. For example, there are no working examples of a compound of instant Formula (I) wherein:
R1 is CN, NRaRb, C2-C6 cycloalkyl, or -O-C3-C6 cycloalkyl and
R5 is C3-C6 cycloalkyl or a 4-6 membered monocyclic heterocyclyl
Thus, the specification is not adequately reflecting the structural diversity of the claimed genus.
In the absence of clear guidance, a person of ordinary skill in the art would require undue experimentation to:
make all compounds comprising structural elements that are outside the scope of the enabling elements listed above and
determine which of those compounds are EGFR inhibitors.
The breadth of the claims
The claims are broad insofar as the instant claims recite a compound of formula (I), wherein the compound can possess a structurally diverse range of chemical groups, that can be used to treat any cancer.
Claims 3-21, and 27, which are dependent on claim 1, are also rejected for further requiring and/or reciting elements that are outside the scope of the enabling elements listed above.
Claim Rejections - 35 USC § 112(a) – Enablement
Claims 21 and 27 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
See the “1. The nature of the invention” subsection of the “Claim Rejections - 35 USC § 112(a) – Scope of Enablement” section above.
State of the prior art
See the “2. State of the prior art” subsection of the “Claim Rejections - 35 USC § 112(a) – Scope of Enablement” section above.
The level of the skill in the art
See the “3. The level of the skill in the art” subsection of the “Claim Rejections - 35 USC § 112(a) – Scope of Enablement” section above.
The presence or absence of working examples; the amount of direction or guidance present; and quantity of experimentation necessary
The prior art recognizes the importance of in vivo tumor models, including the cell line-derived tumor xenograft (CDX) model and the patient-derived xenograft (PDX) model, as standard tools for evaluating the therapeutic efficacy of candidate anticancer agents.
For example, as stated previously, Schalm discloses that oral administration of BLU-945 to tumor-bearing mice demonstrated potent EGFR pathway inhibition and anti-tumor activity at well-tolerated doses in the subcutaneous NCI-H1975 CDX model and osimertinib-resistant CDX and PDX models, as well as in the intracranial luc-H1975 model of NSCLC (see “Results” section, last sentence). Such in vivo data provide evidence that BLU-945 (a compound with a structure similar to the structure of the instant compounds) is capable of treating NSCLC (i.e., not all cancer) in a subject.
In contrast, the instant specification only provides results from biochemical EGFR inhibition assays and an NCI-H1975 pEGFR AlphaLISA assay, both of which are conducted in vitro. In vitro inhibition does not necessarily establish in vivo efficacy, bioavailability, pharmacodynamic activity, or therapeutic effectiveness in a human subject.
Instant claim 21 recites a method of treating a cancer in a subject, comprising administering a subject in need thereof an effective amount of a compound of instant claim 1 or optionally wherein:
the cancer is NSCLC,
the cancer in the subject in need thereof has metastasized,
the cancer is characterized by:
epidermal growth factor receptor EGFR L858R mutation and/or exon 19 deletion
T790M mutation
The cancer is further characterized by epidermal growth factor receptor (EGFR) C797S mutation and/or
The method further comprises administering the subject in need thereof an effective amount of afatinib, osimertinib, erlotinib, or gefitinib.
The language of instant claim 21 encompasses treatment of any cancer as well as treatment of specifically NSCLC in a subject. As stated above, the instant specification does not provide in vivo data demonstrating a method of treating NSCLC or any cancer in an animal xenograft model. Enabling treatment of cancer broadly would require evaluation of the claimed compounds in established in vivo models appropriate for the various cancer types. Such experimentation is not disclosed and would require substantial additional experimentation.
Furthermore, the therapeutic outcome of combining agents (i.e., administering a combination of one of the instant compounds with an effective amount of afatinib, osimertinib, erlotinib, or gefitinib to a subject in need thereof) cannot be assumed based solely on in vitro inhibition data of the instant compound alone. Thus, the instant specification cannot enable the scope of the claimed combination method recited in instant claim 21 in the absence of experimental evidence or sufficient guidance demonstrating that the claimed compounds, when administered to a subject in combination with afatinib, osimertinib, erlotinib, or gefitinib, can achieve therapeutic efficacy in vivo.
Similarly, instant claim 27 recites a method of inhibiting EGFR comprising administering an effective amount of a compound of instant claim 1 to a subject in need thereof. As discussed above, the instant specification only provides in vitro inhibition data of the instant compounds and does not demonstrate that administration of the claimed compounds to a subject results in EGFR inhibition in vivo. Thus, the instant specification cannot enable the scope of instant claim 27 in the absence of in vivo data or sufficient guidance demonstrating that EGFR inhibition occurs in a subject following administration of an instant compound to the subject.
The breadth of the claims
See the “5. The breadth of the claims” subsection of the “Claim Rejections - 35 USC § 112(a) – Scope of Enablement” section above.
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 6-8 and 10-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 6 and 7 recite the limitation “R1 is halogen, OH, =O…” Claims 6 and 7 are dependent on claim 1 which recites “two R1, when attached to the same carbon atom, form =O…” Claim 1 does not state that a singular R1 can be =O. Thus, there is insufficient antecedent basis for this limitation in the claim.
To avoid a 112(b) issue, claims 6 and 7 can be amended as follows:
“…R1 is halogen, OH, or C1-C4 alkyl optionally substituted with one to three halogen and/or two R1, when attached to the same carbon atom, form =O.”
Claim 8 recites the limitation “wherein Ring A is selected from the group consisting of… cyclobutanonyl…” Claim 8 is dependent on claim 1 which recites “Ring A is C3-C6 cycloalkyl…” According to the instant specification, “[t]he term ‘cycloalkyl’ refers to a monocyclic saturated hydrocarbon ring system. Unless otherwise specified, cycloalkyl has from 3-6 carbon atoms. For example, a C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless otherwise described, a ‘cycloalkyl’ has from three to six carbon atoms” (pg. 5, 6th paragraph).
According to the instant specification, the term “cycloalkyl” does not include “substituted cycloalkyls,” yet claim 8 recites that Ring A can be a cyclobutanonyl group (i.e., a substituted cycloalkyl). Thus, there is insufficient antecedent basis for this limitation in the claim.
Currently as written, claim 8 allows Ring A to be substituted (e.g., cyclobutanonyl) wherein the substituted Ring A can further be substituted with R1. However, according to the claim language of claim 1, Ring A is an unsubstituted C3-C6 cycloalkyl, unsubstituted C3-C6 cycloalkenyl, or unsubstituted 5-10 membered heteroaryl that can then be substituted with R1.
To avoid a 112(b) issue, claim 8 can be amended as follows:
“…wherein
Ring A is selected from the group consisting of cyclobutyl and bicyclo[1.1.1]pentanyl
R1 is independently halogen, OH, or C1-C4 alkyl wherein the alkyl represented by R1 or in the group represented by R1 is optionally substituted with 1 to 3 OH or halogen, and/or two R1, when attached to the same carbon atom, form =O
n is 0, 1, 2, 3, 4, 5, or 6”
Claim 10 recites “…Ring A is 1,4-dioxaspiro[4.5]dec-7-enyl.” Claim 10 is dependent on claim 1 which recites “Ring A is… C3-C6 cycloalkenyl…” The specification does not define “cycloalkenyl,” hence, Examiner interprets “C3-C6 cycloalkenyl” to mean an unsaturated, non-aromatic cyclic group containing 3-6 ring atoms wherein all ring atoms are carbon atoms. However, 1,4-dioxazpiro[4.5]dec-7-enyl is a cyclic moiety containing heteroatoms which would be classified as a heterocyclyl group instead. Thus, there is insufficient antecedent basis for this limitation in the claim.
To avoid a 112(b) issue, claim 10 can be amended as follows:
The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the
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moiety is 1,4-dioxazpiro[4.5]dec-7-enyl.
Claims 11 and 12 recite the limitation “Ring A… is optionally substituted with 1 to 3 halogen, [unsubstituted] C1-C4 alkyl, [or] C1-C4 alkyl substituted with OH or C1-C4 alkoxy.” Claims 11 and 12 are ultimately dependent on claim 1 which recites “Ring A is C3-C6 cycloalkyl, C3-C6 cycloalkenyl, or 5-10 membered heteroaryl…”
Currently as written, claims 11 and 12 allow Ring A to be a substituted wherein the substituted Ring A can then later be further substituted with R1. However, according to the claim language of claim 1, Ring A is an unsubstituted C3-C6 cycloalkyl, C3-C6 cycloalkenyl, or 5-10 membered heteroaryl that can then be substituted with R1. Ring A has to be unsubstituted because according to the instant specification, the definitions of “cycloalkyl” and “heteroaryl” do not include substituted cycloalkyls and substituted heteroaryls (see pg. 5, 6th paragraph for the definition of “cycloalkyl” and pg. 5, 7th paragraph for the definition of “heteroaryl”). As stated above, the term “cycloalkenyl” is not defined by the specification. As such, Examiner interprets “C3-C6 cycloalkenyl” to mean an unsubstituted, unsaturated, and non-aromatic cyclic group containing 3-6 ring atoms wherein all ring atoms are carbon atoms. Thus, there is insufficient antecedent basis for this limitation in the claim.
To avoid a 112(b) issue, claims 11 and 12 can be amended as follows:
For claim 11:
“…wherein
Ring A is 5-6 membered heteroaryl;
R1 is independently halogen or C1-C4 alkyl wherein the alkyl represented by R1 or in the group represented by R1 is optionally substituted with 1 to 3 OH;
n is 0, 1, 2, or 3”
For claim 12:
“… wherein
Ring A is thiazolyl, pyrazolyl, or pyridinyl;
R1 is independently halogen or C1-C4 alkyl wherein the alkyl represented by R1 or in the group represented by R1 is optionally substituted with 1 to 3 OH;
n is 0, 1, 2, or 3”
NOTE: “C1-C4 alkoxy” was not included as one of the substituents of R1 as it is considered a non-enabling element (see the “Claim Rejections - 35 USC § 112(a) – Scope of enablement” section above).
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624