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 95-114 are pending. Claims 1-94 are cancelled.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/IB2023/052028, filed on March 4, 2023. This application also claims the benefits of priority to U.S. Provisional Application No. 63/316,740, filed on March 4, 2022.
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).
Applicant is reminded of the proper content of an abstract of the disclosure.
In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics.” Exemplification of a species could be illustrative of members of the class.
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 108, 109, and 112 are objected to because of the following informalities:
In claims 108, 109, and 112:
“and pharmaceutically acceptable salts thereof” should be in singular form instead (as shown below):“and a pharmaceutically acceptable[[s]] salt of any thereof.”
Appropriate correction is required.
Examiner’s note on novelty and nonobviousness
The closest prior art is:
Palmer et al. (Palmer) (WO2016024233A1; published February 18, 2016),
Nguyen et al. (Nguyen) (Nguyen, D. J. M. et al. Targeting the Kynurenine Pathway for the Treatment of Cisplatin-Resistant Lung Cancer. Mol Cancer Res 2020, 18, 105-117), and
Kim et al. (Kim) (Kim, C. et al. A novel dual inhibitor of IDO and TDO, CMG017, potently suppresses the kynurenine pathway and overcomes resistance to immune checkpoint inhibitors. Journal of Clinical Oncology 2019, 37, e14228.)
Novelty:
Novelty with respect to Palmer
Palmer teaches inhibitors of IDO1 and TDO as cancer therapeutics (see abstract). The general structure of the IDO1 and TDO dual inhibitors disclosed in Palmer is as follows:
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(see abstract; herein, referred to as Palmer-Formula-I). The compounds disclosed in Palmer are encompassed by instant Formula I as well. In addition, claim 31 of Palmer recites a method of treating cancer in a warm-blooded animal, including a human, comprising administering to the animal a therapeutically effective amount of a compound of Palmer-Formula-I, as defined in any one of claims 1 to 26 of Palmer, which encompasses the compound of instant formula I. However, Palmer generally teaches treatment of cancer without limiting the method to treatment of refractory cancer. Furthermore, Palmer does not teach nor suggest that the dual IDO1/TDO inhibitory activity of the disclosed compounds is particularly useful or necessary for treating refractory cancer, specifically. In contrast, the instant claims are specifically directed to methods of treating refractory cancer with a dual inhibitor of IDO1 and TDO, which is a distinct therapeutic application of the compounds of instant Formula I that is not disclosed in Palmer. Thus, the instant invention is considered novel with respect to Palmer.
Novelty with respect to Nguyen
Nguyen teaches that IDO1 inhibitors may be more suitable for treating patients with lung cancer who are resistant to cisplatin (see abstract – Implications). However, the IDO1 inhibitors disclosed and tested by Nguyen are not compounds encompassed by instant formula I. Instead, the IDO1 inhibitors tested by Nguyen are Epacadostat, PF-06840003, NLG-919, and indoximod (see pg. 106, left col., “Materials and Methods” section, 1st paragraph, 2nd to last sentence), wherein the four compounds have structures that are not encompassed by instant formula I. Furthermore, Nguyen teaches that their findings have implications in the treatment of cisplatin-resistant lung cancer with IDO1 inhibitors (see abstract – Implications) and does not teach or suggest the use of a dual IDO1 and TDO inhibitor for such treatment. Accordingly, Nguyen does not disclose the presently claimed method of treating refractory cancer in a subject (or preventing the development of refractory cancer in a subject) or a method of treating a refractory cancer cell (or preventing the development of a refractory cancer cell) using a compound of instant formula I (which has dual IDO1 and TDO inhibitory activity). As such, the instant invention is considered novel with respect to Nguyen.
Novelty with respect to Kim
Kim teaches that CMG017, a novel dual inhibitor of IDO and TDO, can overcome resistance to immune checkpoint inhibitors and, therefore, teaches the use of a dual IDO/TDO inhibitor in the treatment of refractory cancer (see title and abstract). However, Kim does not disclose the chemical structure of CMG017 nor does Kim teach/suggest that CMG017 is a compound encompassed by instant Formula I. Furthermore, Kim does not disclose that CMG017 has an IC50 of less than 100µM in both cell-based assay for IDO1 and TDO inhibition assays, as required by the instant claims. Thus, Kim does not disclose all limitations of the claimed invention, and the instant invention is considered novel with respect to Kim.
Nonobviousness:
Nonobviousness with respect to Palmer in view of Nguyen
Nguyen teaches that IDO1 inhibitors may be more suitable for treating patients with lung cancer who are resistant to cisplatin (see abstract – Implications). Although Nguyen does not teach the use of a dual IDO1/TDO inhibitor, a POSITA could have tried to use the IDO1/TDO inhibitors disclosed by Palmer for the treatment of cisplatin-resistant lung cancer because Palmer establishes that these compounds possess IDO1 inhibitory activity (see the table on pg. 67-70 of Palmer), while Nguyen teaches that inhibition of IDO1 can be beneficial in treating cisplatin-resistant lung cancer (see abstract – Implications). However, although it may have been obvious to try the IDO1/TDO inhibitors of Palmer for the treatment of cisplatin-resistant lung cancer, the results of such treatment would not necessarily have been predictable. Nguyen only demonstrates the effect of IDO1 inhibition and does not teach the use of an inhibitor having both IDO1 and TDO inhibitor activity. Thus, Nguyen provides no basis for predicting whether the additional inhibition-of-TDO property would improve, diminish, or otherwise alter the therapeutic effect observed with selective IDO1 inhibition by Nguyen. This unpredictability is consistent with the unexpected results demonstrated by the instant inventors.
The instant inventors demonstrate an unexpected result associated with the use of the claimed dual IDO1/TDO inhibitor. Nguyen tested different IDO1 inhibitors against cisplatin-resistant lung cancer cells and found that epacadostat exhibited the best efficacy for growth inhibition among the IDO1 inhibitors tested (pg. 112, right col., “CR cells were hypersensitive to IDO inhibitors” section, 2nd sentence). In contrast, the instant application directly compares epacadostat with AT-0174 (i.e., compound 66 as recited in instant claims 108-110 and 112-114), a dual IDO1/TDO inhibitor, in a cisplatin-resistant lung cancer mouse model (see instant specification, Example 3, “Results” section on pg. 54). The instant inventors found that AT-0174 induced a significantly greater reduction in tumor size in LLC-CR [i.e., cisplatin resistant mouse cell lines derived from Lewis lung cancer cells] allograft mice compared with epacadostat:
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(instant specification, Fig. 2B). Thus, although the combined teachings of Palmer and Nguyen may have provided a POSITA with a reason to try and use Palmer’s IDO1/TDO inhibitors to treat cisplatin-resistant lung cancer, the prior art did not teach or reasonably predict that the dual IDO1/TDO inhibitor AT-0174 would provide significantly greater antitumor efficacy than selective IDO1 inhibition with epacadostat. Thus, for at least the above reasons, the instant invention is considered nonobvious in view of Palmer and Nguyen.
Nonobviousness with respect to Palmer in view of Kim
Kim teaches that a dual IDO/TDO inhibitor can overcome resistance to immune checkpoint inhibitors (see title and abstract). Therefore, upon learning that the compounds disclosed by Palmer possess dual IDO1/TDO inhibitory activity, a POSITA could have been motivated to try using Palmer’s compounds to treat refractory cancer. However, Kim only demonstrates this therapeutic effect with CMG017, whose chemical structure and specific IDO1/TDO inhibitory potency are not disclosed. Therefore, Kim provides no structure-activity relationship or other guidance from which a POSITA could reasonably predict that the structurally distinct compounds of Palmer would exhibit the same therapeutic effect. Thus, while Kim may have provided a reason to investigate Palmer’s dual IDO1/TDO inhibitors for treating refractory cancer, it would not have provided a reasonable expectation that Palmer’s compounds would successfully treat refractory cancer merely because they also inhibit IDO1 and TDO. Accordingly, the instant invention is considered nonobvious in view of Palmer and Kim.
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.
Scope of Enablement
Claims 95-114 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
The invention as recited in claim 95 except that the points below are changed according to the following:
A method of treating refractory cancer , wherein the refractory cancer is lung cancer or pancreatic cancer, in a subject…
Z is N , W is CR1, X is CR2 and Y is CR3; orX is N , W is CR1, Y is CR3 and Z is CR4 orX and Z are both N , W is CR1 and Y is CR3;
wherein R1, R2, R3, and R4 are as recited in instant claim 95 up to the 2nd line of pg. 3 in the instant claim set or R2 and R3 taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from O, N and S, and the ring is optionally substituted independently with 1 to 4 substituents selected from R;
R9 and R10 are each independently H or Me;
The invention as recited in claim 96 except that the points below are changed according to the following:
A method of treating a refractory cancer cell , wherein the refractory cancer cell is a lung cancer cell or a pancreatic cancer cell…
Z is N , W is CR1, X is CR2 and Y is CR3; orX is N , W is CR1, Y is CR3 and Z is CR4 orX and Z are both N , W is CR1 and Y is CR3;
wherein R1, R2, R3, and R4 are as recited in instant claim 96 up to the middle of pg. 6 in the instant claim set (i.e., up to “… C1-C6 -alkylpiperazinyl, mopholinyl and thiomorpholinyl”) or R2 and R3 taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from O, N and S, and the ring is optionally substituted independently with 1 to 4 substituents selected from R;
R9 and R10 are each independently H or Me;
The method, as recited in claim 97, but being dependent on point (1) above instead of claim 95;
The method, as recited in claim 98, but being dependent on point (3) above instead of claim 97;
The method, as recited in claim 99, but being dependent on point (4) above instead of claim 98;
The method of point (1) above, wherein the refractory cancer is a respiratory tract cancer or a digestive tract cancer, wherein
the refractory cancer of the respiratory tract is selected from: small cell and non-small-cell lung carcinoma and
the digestive tract cancer is pancreatic cancer;
The method of point (1) above, wherein the refractory cancer is selected from lung cancer or pancreatic cancer (i.e., not enabled for: the refractory cancer is a solid tumor);
The method, as recited in claim 102, but being dependent on point (1) above instead of claim 95;
The method, as recited in claim 103, but being dependent on point (8) above instead of claim 102;
The method of point (1) above, wherein R9 and R10 are independently selected from H and Me [i.e., point (10) is essentially the same as point (1)];
The method, as recited in claim 105, but being dependent on point (10) above instead of claim 104;
The method of point (1) above, wherein:
Z is N , X is CR2 and Y is CR3…
X is N , Y is CR3 and Z is CR4…
X and Z are both N , and Y is CR3…
The method of point (1) above, wherein Z is N , X is CR2 and Y is CR3;
The method, as recited in claim 108, but being dependent on point (1) above instead of claim 95;
The method, as recited in claim 109, but being dependent on point (1) above instead of claim 95;
The method, as recited in claim 110, but being dependent on point (1) above instead of claim 95;
The method, as recited in claim 111, but being dependent on point (1) above instead of claim 95;
The method, as recited in claim 112, but being dependent on point (2) above instead of claim 96;
The method, as recited in claim 113, but being dependent on point (2) above instead of claim 96;
A method of treating refractory cancer, wherein the refractory cancer is lung cancer or pancreatic cancer, in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of 6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) or a pharmaceutically acceptable salt thereof, wherein the refractory cancer is refractory to an anticancer agent, and wherein the anticancer agent is a platinum-based chemotherapeutic agent;
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/or 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 to make and use the invention based on the content of the disclosure, 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 the use of a dual inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase (TDO), either alone or in combination with other agents, and pharmaceutical compositions comprising the same in the treatment or prevention of refractory cancer and in the manufacture of a medicament for treating or preventing refractory cancer. The dual inhibitor of IDO1 and TDO have a structure represented by instant Formula I:
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. The variables of instant Formula I are described within the instant specification.
State of the prior art and the predictability or lack thereof in the art
See the “Examiner’s note on novelty and nonobviousness” section above for a discussion of the state of the prior art and an explanation as to why the instant invention is considered novel and nonobvious.
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 breadth of the claims
The claims are broad insofar as the instant claims recite a compound of instant formula I wherein the compound can possess a structurally diverse range of chemical substituents.
The method claims are also broad insofar as they encompass treatment of any refractory cancer which includes, but are not limited to, the list of refractory cancers recited in instant claim 100.
The presence or absence of working examples
The instant specification only provides 28 specific working examples of IDO1/TDO inhibitors (see Table 1 on pg. 48-52). Of these 28 working examples, 26 of them are encompassed by instant formula I (as recited in the instant claims).
Note: Compounds 15B and 4B (see pg. 52 of instant specification for structures) are not encompassed by instant formula I. For example, compound 4B has R9 = H and R10 = -C(O)OPh. However, R10 = -C(O)OPh is not an option according to instant claims 95 and 96. According to instant claims 95 and 96, R10 can be an optionally substituted C1-6 alkyl group, however, it can only be substituted with the substituents explicitly recited in instant claims 95 and 96 which does not include an oxo (i.e., =O) substituent. Therefore, instant compounds 15B and 4B are not encompassed by instant formula I.
Furthermore, the compounds in instant Table 1 are the same compounds disclosed in Palmer (WO2016024233A1; published February 18, 2016). For example, going down the list of compounds recited in instant Table 1:
instant compound 66 corresponds to compound 66 in Palmer,
instant compound 6 corresponds to compound 6 of Palmer,
instant compound 8 corresponds to compound 8 in Palmer, and so on.
Moreover, the instant specification explicitly states:
“Compounds of Formula I may be prepared by following the methods described in PCT International patent application number PCT/IB2015/056129 (published as WO2016024233 [i.e., Palmer]), which is incorporated herein by reference, or procedures analogous thereto. The person skilled in the art would appreciate that other dual inhibitor of IDO1 and TDO are also suitable for use in the invention” (pg. 41, lines 14-18).
Therefore, a POSITA would understand that the compounds of Palmer can also be used in the instant invention.
The instant working examples and the 96 compounds explicitly disclosed in Palmer do not adequately represent the full breadth of the claimed genus which was established to be broad (see “4. The breadth of the claims” subsection above). For example, according to instant claims 95 and 96, the compound of Formula I can be substituted with structurally diverse substituents at any of the positions indicated in instant Formula I. However, in the instant case and among the 96 compounds explicitly disclosed in Palmer, all compound examples possess the following structural features:
Z and/or X are N (not N-oxide);
R2 and R3 being any of the options recited in instant claims 95 or 96 or
R2 and R3 taken together (not “R3 and R4 taken together”) can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from O, N and S, and the ring is optionally substituted independently with 1 to 4 substituents selected from R;
R9 and R10 are each independently selected from H or Me.
Accordingly, significant portions of the claimed structural space remain unexplored by the working examples. The examples, therefore, provide limited information regarding how variations in R9 and R10, for example, affect the compounds’ ability to treat refractory cancer in a subject or to treat a refractory cancer cell.
Additionally, the working examples do not adequately represent the full breadth of the claimed methods of treatment. The instant specification demonstrates that selected compounds can treat refractory lung cancer cells (see instant example 2), refractory lung cancer in a mouse model (see instant examples 3 and 4), and refractory pancreatic cancer in a mouse model (see instant example 5). However, the instant specification does not provide working examples demonstrating therapeutic activity in other refractory cancer types including, but not limited to, the refractory cancers recited in instant claim 100.
Furthermore, the instant specification does not provide any working examples demonstrating the claimed prevention of the development of refractory cancer or prevention of the development of a refractory cancer cell. Although the working examples demonstrate administration of compound 66 (i.e., AT-0174), either alone or in combination with an anticancer agent, to treat cancer that is already refractory (see instant examples 3-5), these examples do not demonstrate that compound 66 prevents a cancer that is initially responsive to an anticancer agent or cancer therapy from subsequently becoming refractory to that agent or therapy. For example, the instant specification does not provide a study in which a cancer that is initially responsive to cisplatin is treated with compound 66, alone or in combination with cisplatin, and subsequently evaluated to determine whether the development of cisplatin resistance is prevented, inhibited, reduced in likelihood, or delayed. Thus, while the working examples provide evidence that compound 66 can treat an already-established refractory cancer (wherein the refractory cancer is lung cancer or pancreatic cancer), they do not provide experimental evidence demonstrating that compound 66 can prevent the development of refractory cancer as claimed.
The amount of direction or guidance present and the quantity of experimentation needed to make and use the invention based on the content of the disclosure
Although the specification provides 26 specific compounds that are encompassed by instant Formula I and also refer to the 96 specific compounds in Palmer as suitable compounds for the instant invention, it provides limited direction and guidance regarding which structural features of the dual IDO1/TDO inhibitors of instant formula I are responsible for treating a refractory cancer (or treating a refractory cancer cell) and how modifications to the dual IDO1/TDO inhibitors (such as modifications of the R9 and R10) affect such a property. In the instant case, all the instant examples and examples disclosed in Palmer have:
Z and/or X are N (not N-oxide);
R2 and R3 being any of the options recited in instant claims 95 or 96 or
R2 and R3 taken together (not “R3 and R4 taken together”) can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from O, N and S, and the ring is optionally substituted independently with 1 to 4 substituents selected from R;
R9 and R10 are each independently selected from H or Me.
Specifically, the specification does not provide guidance regarding the effect of modifying R9 and R10 in treating refractory cancer or treating a refractory cancer cell. The instant specification also does not provide a structure-activity relationship that would allow a POSITA to predict which R9 and R10 of a compound of instant claim 1 would retain or improve the treating-refractory-cancer property of the compound and which features would destroy such a property. Recall that the compounds of instant formula (I) being able to treat a refractory cancer is a novel and nonobvious finding (see the “Examiner’s note on novelty and nonobviousness” section above for details).
Because the claims encompass numerous alternatives for R9 and R10, the required experimentation would involve not mere routine verification of activity but extensive exploration of the claimed genus to identify operative species which involves undue experimentation. Although a POSITA possesses expertise in medicinal chemistry and organic synthesis, such expertise cannot substitute for the absence of guidance in the specification. The issue is not whether a POSITA is capable of synthesizing and testing compounds encompassed by the claims. Rather, the issue is that the specification provides insufficient information to identify which structural modifications (e.g., which combinations of R1, R2, R3, R4, R9, and R10) preserve or improve the treating-refractory-cancer property and which modifications destroy such a property. Consequently, a POSITA would be required to undertake a substantial medicinal chemistry research program to establish the relevant structure-activity relationships before the full scope of the claimed methods could be practiced.
The instant specification also provides limited guidance for practicing the claimed methods across the full scope of refractory cancers encompassed by the claims. As discussed above, the claimed therapeutic use is novel and nonobvious, and the prior art did not establish that dual IDO1/TDO inhibitors would generally be effective for treating refractory cancer across different cancer types. Instead, the prior art only demonstrated efficacy of an IDO1 inhibitor in cisplatin-resistant lung cancer, and the instant specification provides only limited working examples involving refractory lung and pancreatic cancers. A POSITA, therefore, could not reasonably predict that the efficacy of the instant IDO1/TDO inhibitors in refractory lung and pancreatic cancers would translate to efficacy of other refractory cancers having different tissue origins, resistance mechanisms, or tumor microenvironments. Therefore, a POSITA would require undue experimentation to practice the invention across its full scope as they would need to conduct further research to determine whether dual IDO1/TDO inhibitors represented by instant Formula I have therapeutic efficacy in different refractory cancer contexts.
The specification provides even less guidance regarding the claimed prevention of the development of refractory cancer (or refractory cancer cell), as no working example (either in the instant specification or the prior art) demonstrates that a dual IDO1/TDO inhibitor prevents or delays a cancer from becoming refractory to a particular therapy. The specification does not provide sufficient guidance regarding which patient populations should be evaluated, an effective dose or dosing schedule for prevention, when treatment should begin relative to anticancer therapy, how long the inhibitor should be administered, or how long subjects must be monitored to determine whether resistance has been prevented or delayed. A POSITA would therefore need to design and conduct prospective resistance-development studies across the claimed cancers and therapies and empirically determine the appropriate treatment conditions and whether resistance is actually prevented, reduced, or delayed. Since neither the disclosure nor the prior art establishes that dual IDO1/TDO inhibition can predictably prevent the development of refractory cancer, such experimentation across the full scope of the claims would be undue.
Written Description
Claims 95-114 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(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
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, the specification does demonstrate possession of:
A method of treating refractory cancer, wherein the refractory cancer is lung cancer or pancreatic cancer, in a subject according to point (1) as recited in the list of enabling elements as described in the “Scope of Enablement” section above; and
A method of treating a refractory cancer cell, wherein the refractory cancer cell is lung cancer cell or pancreatic cancer cell, according to point (2) as recited in the list of enabling elements as described in the “Scope of Enablement” section above;
because the instant specification provides therapeutic efficacy data specifically for models of lung and pancreatic cancer (lung cancer data: instant examples 2-4; pancreatic cancer data: instant example 5). However, the claims encompass methods of treating any refractory cancer in a subject or treating any refractory cancer cell. The instant specification does not disclose a representative number of methods of treating other refractory cancers (or solid tumors, generally) spanning the breadth of the claimed genus, nor does it demonstrate that efficacy in lung or pancreatic cancer is representative of efficacy across the full scope of refractory cancers or refractory cancer cells. Therefore, the instant specification fails to provide adequate written description support for the full scope of the claimed invention.
Furthermore, the instant working examples and the 96 compounds explicitly disclosed in Palmer (i.e., compounds that are encompassed by instant formula I as explained in the instant specification pg. 41, lines 14-18) do not adequately represent the full breadth of the claimed genus which was established to be broad (see “4. The breadth of the claims” subsection of “Scope of Enablement” section above). For example, according to instant claims 95 and 96, the compound of Formula I can be substituted with structurally diverse substituents at any of the positions indicated in instant Formula I. However, in the instant case and among the 96 compounds explicitly disclosed in Palmer, all compound examples possess the following structural features:
Z and/or X are N (not N-oxide);
R2 and R3 being any of the options recited in instant claims 95 or 96 or
R2 and R3 taken together (not “R3 and R4 taken together”) can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from O, N and S, and the ring is optionally substituted independently with 1 to 4 substituents selected from R;
R9 and R10 are each independently selected from H or Me.
Accordingly, significant portions of the claimed structural space remain unexplored by the working examples. According to MPEP § 2163 (see above), R9 and R10 being H or Me, for example, do not adequately reflect a claimed genus that encompasses a compound of instant formula I wherein R9 and R10 is independently selected from the long list of alternatives recited in instant claims 95 and 96. Likewise:
Z and/or X being N does not adequately reflect a claimed genus that encompasses a compound of instant formula I wherein Z and/or X is N-oxide; and
R2 and R3 taken together to form a ring structure (as described above) does not adequately reflect a claimed genus that encompasses a compound wherein R3 and R4 are taken together to form a ring structure instead.
Accordingly, the disclosed species do not adequately reflect the structural diversity of the claimed genus and, therefore, do not demonstrate possession of the full scope of compounds recited in instant claims 95-114.
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
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