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 .
Status of the Claims
Claims 1-10, 12, and 14-19 are pending. Acknowledgment is made of Applicant’s cancelation of claims 11 and 13 in the amendment filed on August 21, 2024.
Election/Restrictions
Applicant’s election without traverse of Compound QE-18-WG07 (herein Compound QE) of formula I depicted below and hepatocellular carcinoma in the reply filed on April 9th, 2026 is acknowledged.
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Compound QE is a compound of formula I, depicted below, wherein:
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X is NH;
Y represents the following, with R5 = H, R6 = NO2, and R7 = OH; and
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Z represents the following, with R1 = OCH3 and R2, R3, and R4 all H.
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Compound QE is also recited in claim 15 (p. 13, row 5 of table).
Claim 10 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 9th, 2026.
Claims 1-9, 12, and 14-19 are under examination as they relate to compounds of formula I and the elected species compound QE.
Priority
This application claims priority to U.S. Provisional Application No. 63/228,240, filed August 2nd, 2021 and is a 371 of PCT/SG2022/050551, filed August 2nd, 2022.
Claim Rejections – Improper Markush
Claims 1-9, 12, and 14-19 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of compounds represented by Formula I in claim 1 is improper because the alternatives defined by the Markush grouping do not share both a substantial structural feature and a common use for the following reasons:
The Markush grouping in claims 1-9, 12, 14, and 16-19 is directed to compounds of Formula (I), depicted below:
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With the myriad of compounds that arise from the various definitions and combinations of the variables present in this formula, the result is a group of compounds that include a variety of substitution patterns that are not obvious variants of each other. To this end, a comparison of three compounds of Formula (I) presented in the specification (Table 6A, pp. 68-73) demonstrates a lack of significant structural similarity and shows compounds of the formula (I) recited in instant claim 1 are not obvious variants of each other:
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(p. 68, row 3)
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(p. 69, row 5)
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(p. 70, row 6)
As for the Markush grouping in claim 15, the compounds do not all share a common structure, as evidenced by the following compounds:
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(p. 12, row 1)
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(p. 17, row 4)
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(p. 18, row 2)
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
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 1-9, 12, and 14-15 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 method of treating hepatocellular carcinoma or lung cancer comprising administering a compound of formula (I), does not reasonably provide enablement for a method of treating any cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, state and predictability of the art, and relative skill of those in the art
The invention relates to a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of formula (I).
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art of treating any cancer, the examiner cites Gura et al ("Systems for Identifying New Drugs are Often Faulty"); Johnson et al. ("Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials"); and Kunnumakkara et al (“Cancer drug development: The missing links”).
Gura, cited for evidentiary purposes, teaches that researches face the problem of sifting through potential anticancer agents to find ones promising enough to make human clinical trials worthwhile and further teach that since formal screening began in 1955, many thousands of drugs have shown activity in either cell or animal models, but only 39 have actually been shown useful for chemotherapy (see page 1041, first and second paragraph). Also, with regard to unpredictability, Johnson, also cited for evidentiary purposes, teach that the in vivo activity of 39 different agents in a particular histology in a tumor model did not correlate to activity in the same human cancer (see Results on page 1426). 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. Further, the mode of action of anticancer agents is often unknown or very unpredictable and administration of such agents is often accompanied by undesirable side effects.
Furthermore, with regard to unpredictability, Kunnumakkara, cited for evidentiary purposes, teaches cancer is a group of more than 200 neoplastic diseases caused by diverse deregulated cell signaling cascades (page 633, left, 1st paragraph); consumption of tobacco and alcohol, obesity, insufficient physical activity, exposure to ultraviolet radiation, and various dietary factors which include insufficient fruit, non-starchy vegetables, and fiber; red/processed meat are predicted to be strongly associated with the risk of diverse cancer types; cancer occurs as a result of the dysregulation of as many as 500 different genes which may happen over a very long duration of time (20–30 years) till the symptoms become apparent (page 633, right, last bridge paragraph). Kunnumakkara further teaches there exists a missing connection between preclinical data and clinical findings; although, a significantly huge amount of money is spent in the pre-clinical settings for target validation and drug optimization, most of the therapies fail in the clinical trials till date; this can be due to the reason that the models used in the pre-clinical setting are not the adequate ones to effectively mimic human responses (page 664, right, 2nd paragraph); although highly convenient, cancer cell line models are associated with several limitations as well; for example, existence of genomic instability which may result in differences between the original tumor and the respective cell line, culture conditions that can alter the morphology, gene expression pattern, genomic profile, cellular pathways and culture environment from that of the original tumor, loss of natural tumor heterogeneity; the generic transformations that occur upon culturing of the cancer cells are not restored when regrown in vivo; and cancer cells in the in vitro condition grow in absence of stroma which include lymphatic vessels and blood, associated fibroblasts and immune cells, and lack a complex extracellular matrix; therefore, in vitro data often exhibits fundamental mismatch with those obtained from clinical findings and hence this can be regarded as one prime reason behind the failure of novel drug development (page 665, last bridge paragraph). Kunnumakkara teaches the foremost shortcomings of the use of animal models are their inability to recapitulate the link between the tumor and its microenvironment completely and the requisite of an immunocompromised host; basically, these animal models do not have the ability to reflect all the features of human cancer impeccably. Kunnumakkara teaches despite the advances in understanding of cancer biology and deriving different novel therapeutic targets, the translation of these understanding into therapies is poor due to higher failure rate (90%). The high failure rate could be due to non-consideration of factors such as clinical translation, drug delivery, drug pharmacokinetics, pre-clinical models, and tumor physiology, which are critical factors.
These articles plainly demonstrate that the art of developing and testing anticancer drugs, particularly for use in humans, is extremely unpredictable, particularly in the case of a single compound or genus of compounds being used to treat any and all cancers.
2. The breadth of the claims
Claims 1-9 and 11-15 are very broad in terms of the type of diseases being treated: all cancers are claimed to be treated with a compound of formula I.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides in vitro data highlighting the importance of SALL4B for the survival of SALL4-positive HCC (hepatocellular carcinoma) and lung cancer cells (Example 5, pp. 56-57) and the activity of 35 compounds of formula I against SALL4B (Example 9, p. 67-69 and Tables 6A and 6B). Furthermore, the specification provides data for QE-18-WG07, a compound of formula (I), in a SALL4-high HCC mouse xenograft model (Example 15, pp. 85-86). However, a single compound in a single cancer is insufficient to support enablement for the full scope of diseases encompassed by the scope of the claims, namely the treatment of any type of cancers in a subject. The specification provides no particular direction or guidance for determining the particular administration regimens (e.g., timing, administration routes, etc.) necessary to treat all of the various diseases encompassed by the claims, particularly in humans.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that Examples 5, 9, and 15 could be predictably used to treat all types of cancers. Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent 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" (42 USPQ 2d 1001, Fed. Circuit 1997).
As noted above, the specification provides no experimental support for the treatment of any cancer. A review of the state of the art fails to reveal that compound QE-18-WG07 is useful as therapeutic for the treatment of any cancer within the scope of the instant claims. Determining if any particular claimed compound would treat any particular cancerous disease state would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicants. As noted supra, even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy.
Accordingly, claims 1-9, 12, and 14-15 do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-9, 12, 14-16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Sueoka et al. (Surgery, Volume 155, Issue 4, 2014, Pages 640-649) in view of Fajas et al. (WO 2010/092440), as evidenced by CAS Registry No. 182498-30-2.
Sueoka teaches that blocking CXCR2 clearly suppresses the growth of intrahepatic cholangiocellular carcinoma (ICC) and that blocking CXCR2 may be a promising therapeutic approach for ICC (abstract, header “Conclusion). In particular, Sueoka teaches injections with SB225002, a CXCR2 antagonist, significantly suppressed tumor growth in mice (p. 645, left col., para. 2, lines 10-11). Sueoka also teaches ICC is a form of liver cancer (p. 640, left col., para. 1).
Sueoka does not teach instantly claimed Compound QE is a CXCR2 receptor antagonist.
Fajas teaches N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea is a CXCR2 receptor antagonist (claim 5, line 30 of p. 39). As evidenced by CAS Registry No. 182498-30-2 (p. 2, section “Other Names and Identifiers”), this is a name for the below compound, which is the same as instant Compound QE:
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Fajas also teaches a method of administering a CXCR2 receptor antagonist to a subject, including compound QE (claim 11; this teaches administering compounds from Fajas claims 1-6, which includes compound QE from claim 5).
Regarding claims 1-9, 12, 14-16, and 18, it would have been prima facie obvious before the effective filing date of the present invention for a person of ordinary skill in the art to administer compound QE to treat liver cancer. One would have been motivated and had a reasonable expectation to do so given Sueoka teaches administering CXCR2 receptor antagonist suppresses ICC tumor growth and teaches that blocking CXCR2 may be a promising therapeutic approach for ICC, and given Fajas teaches compound QE is a CXCR2 receptor antagonist that can be administered to a subject. It would have been obvious to substitute one functional equivalence (any CXCR2 antagonist) for another (Compound QE) since the prior art establishes that both function in similar manner (both block CXCR2 and both can be administered to a subject).
Taken all together, this would result in the practice of claims 1-9, 12, 14-16, and 18 with a reasonable expectation of success.
Claims 1-9, 12, 14-16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng et al. (Molecular Cancer (2021) 20:62, published April 04, 2021) in view of Fajas et al. (WO 2010/092440), as evidenced by CAS Registry No. 182498-30-2.
Cheng teaches CXCR2 is elevated in human lung cancer tissues and correlates with poor prognosis (p. 5, left col.). Cheng also teaches that treatment with SB225002, a selective CXCR2 inhibitor, led to a reduction of tumor growth in both orthotopic and subcutaneous tumor models of lung cancer (p. 7, right col., para. 3, lines 5-10).
As discussed supra, Fajas teaches N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl) urea is a CXCR2 receptor antagonist (claim 5), which is the same as instant Compound QE as evidenced by CAS Registry No. 182498-30-2.
Regarding claims 1-9, 12, 14-16, and 18, it would have been prima facie obvious before the effective filing date for a person of ordinary skill in the art to administer compound QE to treat lung cancer. One would have been motivated to do so given Cheng teaches a method of treating lung cancer in a subject comprising administering a CXCR2 receptor antagonist and given Fajas teaches compound QE is a CXCR2 receptor antagonist that can be administered to a subject. It would have been obvious to substitute one functional equivalence (any CXCR2 antagonist) for another (Compound QE) since the prior art establishes that both function in similar manner (both block CXCR2 and both can be administered to a subject).
Taken all together, this would result in the practice of claims 1-9, 12, 14-16, and 18 with a reasonable expectation of success.
Claims 1 and 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng et al. (Molecular Cancer (2021) 20:62, published April 04, 2021) in view of Fajas et al. (WO 2010/092440) as applied to claims 1, 15-16, and 18 above, and further in view of Li et al. (Journal of Experimental & Clinical Cancer Research (2015) 34:129).
As discussed above, Cheng teaches CXCR2 is elevated in human lung cancer tissues and correlates with poor prognosis. Cheng teaches CXCR2+ TANs (neutrophils) significantly infiltrated into tumor tissue of mice (p. 7, right col., para. 2) and that treatment with SB225002, a selective CXCR2 inhibitor, led to a reduction of tumor growth in both orthotopic and subcutaneous tumor models of lung cancer.
Cheng does not teach the correlation of CXCR2 with prognosis of liver cancer.
As discussed above, Fajas teaches Compound QE is a CXCR2 inhibitor. Fajas does not teach the role of CXCR2 in liver cancer.
Li teaches CXCR2+ cell density is an independent prognostic factor for predicting OS for HCC patients and that the CXCR2-CXCL1 axis can regulate neutrophil infiltration into HCC tumor tissues and might represent a useful target for anti-HCC therapies (p. 1, Abstract box, section “Conclusions”).
Regarding claims 17 and 19, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to administer compound QE to treat hepatocellular carcinoma. Since Cheng teaches CXCR2 elevated CXCR2 expression is associated with poor prognosis in lung cancer and inhibition of CXCR2 treats lung cancer and Fajas teaches compound QE is a CXCR2 inhibitor, one would be motivated and had a reasonable expectation of success to use the same strategy of administering compound QE as a CXCR2 inhibitor to treat HCC since Li teaches elevated CXCR2 expression is also associated with poor prognosis in HCC and suggests the CXCR2-CXCL1 might represent a useful target for anti-HCC therapies.
Taken together, all this would result in the practice of claims 17 and 19 with a reasonable expectation of success.
Conclusion
Claims 1-9, 12, and 14-19 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OLIVER D. HEES whose telephone number is (571)272-9840. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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/O.D.H./Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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