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 .
Non-Final Rejection
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 28 October 2025 has been entered.
Applicant’s Response to Final Office Action
Applicant’s response, dated 28 October 2025, to the final rejection dated 28 August 2025 has been received and duly noted. Amended claims have been received and entered into the record.
Terminal Disclaimers Previously Filed
For clarity of the record the Examiner reiterates that a terminal disclaimer was filed on 01 August 2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of:
Any patent granted on Application Number 18488912;
Any patent granted on Application Number 18530017;
US Patent 1188338;
US Patent 10632209;
US Patent 11110177;
US Patent 11147885;
US Patent; 11786602;
US Patent; 11833210;
The terminal disclaimer has been reviewed and accepted. The terminal disclaimer has been recorded.
Examiner’s Response
Unless re-stated herein any outstanding ground of objection or rejection is withdrawn for the reasons stated in Applicant’s response.
The present office action replaces all prior versions or listing of rejections in the present application.
Election/Restrictions
Scope of Search
The Examiner has followed the guidelines found in MPEP 803.02 regarding the provisional election of species and the search and examination of the Markush generic claims:
“Should applicant, in response to a rejection of a Markush claim, overcome the rejection by amending the Markush claim to exclude the species anticipated or rendered obvious by the prior art, the amended Markush claim will be examined again. The examination will be extended to the extent necessary to determine patentability of the Markush claim. In the event prior art is found during this examination that anticipates or renders obvious the amended Markush claim, the claim will be rejected and the action can be made final…”
Applicant’s amendment has excluded from scope the species cited in the previous office action. The search has been further extended to encompass the species cited in the prior art rejection below. The search has not been extended unnecessarily to cover all nonelected species.
Status of the Claims
Claims 1, 3, 5-6, 13-14 and 16-17 are pending and rejected.
Claims 2, 4, 7-12, 15 and 18 were previously cancelled by the Applicant.
Claim Interpretation
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Independent claim 1 has been amended by adding the following limitation:
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This is construed consistently with the examples of the specification and the plain meaning of the phrase “1 and 3 positions”, as it relates to the D ring - as requiring that the substituents be at ring D atoms which are at the 1 and 3 positions relative to each other.
For instance, in example compounds 43 and 44, while the substituents may be at the 2,5- and 2,4- positions of the thiophene ring if the sulfur atom is considered to be atom number 1, relative to each other the -C(=S)NH2 group and the bond to the phenyl ring (A) are at positions 1 and 3:
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The same is also true for examples 155-156 where the substituents may be at the 2,4- and 2,6- positions of the pyridine ring, if the nitrogen atom is considered to be atom number 1, while relative to each other the -C(=S)NH2 group and the bond to the indole ring are at positions 1 and 3:
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Claim Objections
Claims 1 and 13 are objected to over an informal issue.
In claim 1, several underlined text sections are included which are left over from the previous amendment. For example, the phrase “wherein the compound is not compound 1” is underlined. However, this text was already present in the last version and is not newly added.
Claim 13 is identified as “currently amended”, however, no amendment has been made in the current claims listing.
Applicant should ensure that any strikethrough and underlining present in the claims listing refers only to newly added or deleted subject matter and that all the claim status identifiers are correct and current.
Claim Rejections - 35 USC § 112
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.
Claim 3 is 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 is maintained.
Claim 3 depends from claim 1 and lists species, which are outside the scope of the genus of compounds according to formula I-E, as claim 1 has been amended. There is insufficient antecedent basis for these limitations in the claims.
At least 5 of the species listed in amended claim 3 remain outside the scope of independent claim 1. See at least compounds 132-135 and 165:
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Compounds 132-135 lack the A/E ring system required by formula (1-E).
Compound 165 does not comply with formula (1-E) since it does not have a required -C(=S)NH2 group.
Applicant should carefully review the structural formulae of claim 3 to ensure that all of the structures are within the scope of the claim from which it depends.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is maintained.
Claim 3, as presently amended, recites at least 5 species which fall outside the scope of the genus of amended claim 1. Therefore, the claim fails to include all the limitations of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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.
Claims 1, 6 and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Antonini (J. Med. Chem. 1981, 24, 10, 1181–1184, listed on the IDS 04/11/2024).
Antonini discloses administration of the compound “1a”, by injection, to a mouse suffering from cancer, wherein the cancer is leukemia.
See the structure of the compound 1a at chart I on page 1183:
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This is a species of the Markush genus of examined formula (I-E), wherein: X is S; R1 is H; D is a 6-membered heteroaryl ring, A is 6-membered heteroaryl ring and E is absent; the RD1-RD5 and RA1-RA5 substituents are either absent or are each J and J is H, and relative to each other the -C(=S)NH2 group and the bond to ring (A) are at positions 1 and 3 of the (D) ring.
The “Biological Activity and Discussion” section on page 1182 discloses the method of treatment: “The compounds were screened against P-388 lymphocytic leukemia in mice by the Istituto di Ricerche Farmacologiche “Mario Negri”, Milan (Italy). CDF1 mice were injected ip with 106 P-388 lymphocytic leukemia cells on day 0 and were treated ip with a suspension in klucel or in saline and Tween 80 of the specific drug dose on days 1, 5, and 9”.
Results are shown in table I on page 1182 demonstrating effectiveness for compound 1a.
Regarding claim 6 the administering is by injection.
Regarding claim 13 the cancer is leukemia.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 5, 14 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Antonini (J. Med. Chem. 1981, 24, 10, 1181–1184) as applied to claims 1, 6 and 13 above, and further in view of the teachings therein.
The Claims
The examined claims are drawn to a method of treating a subject suffering from cancer, with a compound of formula (1-E).
Claim 5 requires oral administration.
Claim 14 requires that the cancer is a leukemia selected from AML, ALL, Mixed Lineage Leukemia or a leukemia with Partial Tandem Duplication of MLL.
Claim 16 requires that the compound is co-administered with another therapeutic agent.
Claim 17 requires that the subject is a human.
The Prior Art
Antonini discloses compounds and teaches a method of treating cancer with the disclosed compounds. See, for example, at least administration of the species of the compound “1a”, by injection, to a mouse suffering from cancer, wherein the cancer is leukemia.
See the structure of the compound 1a at chart I on page 1183.
This is a species of the Markush genus of examined formula (I-E), wherein: X is S; R1 is H; D is a 6-membered heteroaryl ring, A is 6-membered heteroaryl ring and E is absent; the RD1-RD5 and RA1-RA5 substituents are either absent or are each J and J is H, and relative to each other the -C(=S)NH2 group and the bond to ring (A) are at positions 1 and 3 of the (D) ring.
The “Biological Activity and Discussion” section on page 1182 discloses the method of treatment: “The compounds were screened against P-388 lymphocytic leukemia in mice by the Istituto di Ricerche Farmacologiche “Mario Negri”, Milan (Italy). CDF1 mice were injected ip with 106 P-388 lymphocytic leukemia cells on day 0 and were treated ip with a suspension in klucel or in saline and Tween 80 of the specific drug dose on days 1, 5, and 9”.
Results are shown in table I on page 1182 demonstrating effectiveness for compound 1a. See also the abstract which teaches that the compound also has effectiveness against other cancer cell lines lymphocytic leukemia L-1210 and sarcoma S180 in culture.
Differences between Prior Art & the Claims
The reference discloses a claimed compound as being effective against several cancers, including a lymphocytic leukemia cell line but does not disclose either administering the compound together with an additional therapeutic agent, or administering the compound to a human, by oral or injection administration in order to treat a cancer, such as ALL.
Prima Facie Obviousness, Rational & Motivation
The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. The Court quoting In re Kahn, 441 F.3d 977, 988, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006), stated that “[R]ejections on obviousness cannot be sustained by mere conclusory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.’” KSR, 550 U.S. at___, 82 USPQ2d at 1396. Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield
predictable results;
(B) Simple substitution of one known element for another to obtain predictable
results;
(C) Use of known technique to improve similar devices (methods, or products)
in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) “Obvious to try” – choosing from a finite number of identified, predictable
solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in
either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP § 2143 for a discussion of the rationales listed above along with examples illustrating how the cited rationales may be used to support a finding of obviousness. See also MPEP § 2144- §2144.09 for additional guidance regarding support for obviousness determinations.
The aforementioned reasons above describe rationales that support a conclusion of obviousness based upon the KSR International Co. v. Teleflex Inc. decision.
Here, at least rationale (G) is employed:
Regarding claim 5, it would have been obvious to one skilled in the art at the time of the effective filing of the examined invention to have administered the disclosed effective anti-leukemia compound by oral administration, at least in order to provide for a more convenient means of administration. Oral administration is one of only several possible techniques from which to select for drug administration. Oral administration would be preferred over injection since an oral preparation such as a pill or capsule is easier to use and more shelf stable etc. A skilled artisan would thus have good reason to explore oral administration of a known effective agent such as compound 1a and would expect that some level of effectiveness could be achieved through such administration.
Regarding claim 14, it would have been obvious to one skilled in the art at the time of the effective filing of the examined invention to have administered compound 1a to treat common clinically occurring forms of leukemia, such as ALL. The compound was tested using two different leukemia cell lines and found to be active. One of the cell lines was a lymphocytic variant. A skilled artisan would thus have good reason to use the compound against other types of leukemia, such as ALL. The artisan would expect the compound to provide for a beneficial effect in the treatment of a variety of leukemias in view of the demonstrated effectiveness in two different leukemias and a sarcoma.
Regarding claim 16, it would have been obvious to one skilled in the art at the time of the effective filing of the examined invention to have administered the disclosed effective anti-leukemia compound 1a together with an additional anticancer therapeutic agent in order to provide for a more effective treatment. The combination of the disclosed anticancer agent with another anticancer agent would be obvious to a skilled artisan. MPEP 2144.06 “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”. Thus, a combination of the reference anticancer agent with one or more other known anticancer agents would be expected to provide for a composition which could be administered to treat a broader spectrum of cancers, etc.
Regarding claim 17, it would have been obvious to one skilled in the art at the time of the effective filing of the examined invention to have administered the disclosed effective anti-leukemia compound 1a to a human at least in order to evaluate its clinical effectiveness. The compound is taught as an investigational anticancer agent and is shown to be effective against several cell lines and successfully tested for in vivo activity in a small mammal. A skilled artisan would find good reason in these teachings to use the compound to treat a human patient. One would reasonably expect to achieve some level of effectiveness in the treatment of a human patient with the compound in view of its effectiveness in a mammal.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANIEL R CARCANAGUE whose telephone number is (571)270-3023. The examiner can normally be reached 9 am to 5 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on (571)270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DANIEL R CARCANAGUE/Primary Examiner, Art Unit 1621