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 .
Amended
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(Only) Ten new claims 59-69 depending on examined claim 31 are added.
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.
Previously presented rejection of claim(s) 31, 49-57 59-69 rejected under 35 U.S.C. 103 as being unpatentable over Catarinella, Angew Chem Int Ed Engl. 2009;48(48):9072-6; Tovini ,EMBO reports 21: e50322 | 2020; Wordeman, The Journal of Cell Biology, Vol. 179, No. 5, December 3, 2007 869–879; Ettl, Breast Care 2016;11:174–176; Janssen, Current Biology 28, 2685–2696, 2018 and Orr, 2016, Cell Reports 17, 1755–1763, is maintaintained for reasons of record. Additional references Janssen and Orr are new references, invoked in view of amendments to claims and to augment pending rejection.
Amendments to claims and Applicants arguments are considered.
Applicants arguments focus on the following:
According to Applicant
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(emphasis added by the Examiner).
According to Applicant
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(emphasis added by the Examiner).
Further, Applicant argues
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Applicants arguments are not persuasive.
Catarinella teaches, BTB-1: a small molecule inhibitor of the mitotic motor protein Kif18A.
BTB-1, Fig. 1 at page 9073
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corresponds to instant Formula I compound, wherein R1 = Cl, R2 = phenyl,
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Thus Catarinella is anticipatory with regards to first of the two compounds of the claimed combination.
Tovini teaches (the commercially available) UMK57
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(see claim 50 for structure)
corresponding to
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Thus Tovini is anticipatory with regards to second of the two compounds of the claimed combination.
How the teachings of Catarinella and Tovini correspond to the preamble of the base claim 31 are discussed extensively in the previous action.
As per MPEP a claim preamble (like "A composition comprising...") sets the stage but only limits the claim if it adds essential structure or "gives life, meaning, and vitality" to the claim, otherwise it's just a statement of purpose (e.g., "A composition for treating disease..."). For compositions, it defines the type of substance, but the key is whether the body (after "comprising") clearly defines all the essential components, making the preamble a mere introduction or a crucial structural boundary. Further as per MPEP 2129 Admissions as Prior Art [R-07.2022]. In this context as per MPEP 2111.02 Effect of Preamble [R-07.2022], PREAMBLE STATEMENTS LIMITING STRUCTURE, requirement, consideration of the preamble by the Examiner is evidenced by the extensive discussion of the (inherent) biochemical properties of the essential structural/compound limitations of the base claim, which explains that the prior art structure(s) which is/are capable of performing the intended use as recited in the preamble of the claim.
Applicant restating the compound limitations (italicized at pages 12-15) is just not persuasive.
At page 15, applicant further adds that the cited references do not teach the synergistic effect of the combination. In this context , it is clear that Applicant overlooks argument presented by the Examiner in previous action at page 6 first full paragraph.
Applicants argument that the combination therapy for the intended synergistic effect (without troublesome side effect) is not possible with conventional doses. Examiner cannot overlook Examination guidelines discussed here and in the previous action with regards to combination of previously known claimed elements:
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to combine the instant ingredients for their known benefit since each is well known in the art for their beneficial properties. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. The differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Again, the invention is a selective combination of the inventions by the prior arts done in a manner obvious to one of ordinary skill in the art. Patent for the combination of known elements wherein their functions remain the same withdraws “what is already known into field of its monopoly and diminishes resources available to skilled men”. Sakraida v. Ag Pro, Inc.189 USPQ 449, 425 US 273, (1976). As stated by the Court in KSR International Co., v. Teleflex Inc., 127 US 1727 (2007), “when a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious” (quoting Sakraida v. AG Pro, Inc., 425 US 273 (1976)). And as indicated by the court in Sundance, Inc. v. DeMonte Fabricated, Ltd., 550 F.3d 1356 (Fed. Cir. 2008), a claimed invention is obvious if it is a combination of known prior art elements that would reasonably have been expected to maintain their respective properties or functions after they had been combined. It is prima facie obvious to combine individual ingredients for their known function. In re Linder, 173 USPQ 356; In re Dial, 140 USPQ 244.
Limitations of the new claims 59-62. 64-67, are drawn to dose, and routes of administration and routinely used excipient in the pharmaceutical composition. The are part of well within the routine optimization exercise of one of kill in the pharmaceutical art. According to MPEP) § 2112.01(IV), a claim to a known drug containing a previously known excipient does not render the combination patentable merely because the specific combination had not been described. New claims 63, 68, 69 are drawn to aspects of microtubule turnover, chromosomal instability, limitations specifically addressed in the previous action. In addition, according to Janssen, tilted Loss of Kif18A Results in Spindle Assembly Checkpoint Activation at Microtubule-Attached Kinetochores, teaches subject matter of the preamble in this claims throughout, see column A, page 2685 ‘missegregation of chromosomes compromises cellular fitness and drives chromosomal instability, a major hallmark of cancer cells’. Likewise, with respect to the agent that promotes microtubule turnover the (instant) UMK57, in addition to previously pointed out knowledge, Orr titled ‘Adaptive Resistance to an Inhibitor of Chromosomal Instability in Human Cancer Cells’ teaches, that UMK57 potentiates MCAK in vivo; UMK57 transiently suppresses chromosome missegregation; in CIN cancer cells; CIN cancer cells display adaptive resistance to UMK57; Rate of adaptive resistance in UMK57-treated cells is Aurora B-dependent.
Each ingredient is known in the art; the claimed combination of composition as a whole would have been obvious in view of the cited references. As such there is nothing unobvious in the claims.
Previously presented rejection:
Catarinella teaches, BTB-1: a small molecule inhibitor of the mitotic motor protein Kif18A.
BTB-1, Fig. 1 at page 9073
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same as the dependent compound of claim 48, R1 = Cl, R2 = phenyl.
Kif18A inhibitors are known in the art, for example compounds of claim 58 (see more on this below)
Catarinella teaches a method of inhibiting proliferation of chromosome instable cancer cells (pg 9073, col 1, para 1). The survival and development of each organism relies on the equal partitioning of its genome during cell division. Errors in this process can lead to severe developmental defects and cancer in humans; see also pg 9073, col 2, para 1, BTB-1 is the first inhibitor for Klf1BA, a key enzyme essential for proper chromosome segregation in eukaryotes ranging from yeast to human.
BTB-1 inhibits Kif1BA in an adenosine triphosphate(ATP)-competitive but microtubule-uncompetitive manner and slows down the progression of cells through mitosis) at a dosage effective to inhibit proliferation of said chromosome instable cancer cells (pg 9073, Figure 1b, 1c). BTB-1 is a potent, selective and reversible mitotic motor protein Kif18A inhibitor with an IC50 of 1.69 μM
The survival and development of each organism relies on the equal partitioning of its genome during cell division. Errors in this process can lead to severe developmental defects and cancer in humans; pg 9073, col 1, para 1,
BTB-1 is a potent, selective and reversible mitotic motor protein Kif18A inhibitor with an IC50 of 1.69 μM
Tovini teaches, restoring proper chromosome segregation and preventing ageing" by
Tovini teaches an agent that promotes microtubule turnover (pg 1, col 3, para 1: “The ability of the cell to release faulty attachments relies on kinesin-13 proteins, which promote microtubule depolymerization and turnover, allowing the formation of new chromosome-microtubule attachments; see also pg 2, col 1, para 1, A recently developed method to restore kinesin-13 function relies on the small molecule UMK57 (also see specification page 7, [0021]-[0022], UMK57), which potentiates the activity of MCAK and rescues chromosome segregation errors in the chromosomally unstable cancer cells) and ii would have been obvious to a person having ordinary skill in the art to administer the agent of Tovini in conjunction with the inhibitor of Catarinella because Catarinella teaches a method of inhibiting proliferation of chromosome instable cancer cells (pg 9073, col 1, para 1.
UMK57 is dependent compound of claim 50
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Tovini teaches at page 2, column 1 that it has been demonstrated that a low dose of UMK57 can also rescue age-associated CIN without affecting normal mitotic progression of both old and young cells) and combining the method of reducing proliferation of chromosome instable cancer cells with the method of reducing choromosome instability could provide increased efficacy over either method alone.
Wordeman teaches MCAK facilitates chromosome movement by promoting kinetochore microtubule turnover. Wordeman teaches wherein the agent that promotes microtubule turnover (MCAK itself) is a microtubule destabilizing agent (abstract, Mitotic centromere-associated kinesin (MCAK)/Kif2C is the most potent microtubule (MT)-destabilizing enzyme identified thus far... that MCAK increases the turnover of kinetochore MTs at all centromeres to coordinate directional switching between sister centromeres and facilitate smooth translocation. Wordeman further teaches wherein the microtubule destabilizing agent is consisting of MCAK (pg 874, col 2, para 2, The experiment is diagrammed in Fig. 5 C. Cells expressed our experimental chimeric constructs for 20 h. They were then incubated in 2.5 M nocodazole for 90 min to disassemble all of the MTs and permit all glu-tubulin dimers to be relyrosinated. The cells were then washed free of nocodazole to allow the reformation of MTs and were incubated in MG132 for either 20 or 120 min to arrest the cells in metaphase).
Nocodazole is compound of dependent claim 52.
Ettl teaches that palbociclib is a CDK4/6 Inhibitor in Clinical Practice for the Treatment of Advanced HR-Positive Breast Cancer; palbociclib targets cell cycle machinery. CDK4/6 inhibitor specifically targets and inhibits cyclin-dependent kinases 4 and 6 (CDK4/6). These kinases play a crucial role in cell cycle regulation, particularly during the G1 to S phase transition. By inhibiting CDK4/6, palbociclib can halt the progression of cancer cells through the cell cycle, slowing down or stopping their proliferation. Abstract.
Palbociclib is compound of claim 55-57.
As to the KIF18A inhibitors of claim 58. These are known in the disclosure of WO 2020132651 (priority date 2018-12-20). See section under 35 USC § 112-2. Also see applicant admitted to prior art at page 14, [0044].
This rejection is based on the well-established proposition of patent law that no invention resides in combining old ingredients of known properties where the results obtained thereby are no more than the additive effect of the ingredients, In re Sussman, 136 F.2d 715, 718, 58 USPQ 262, 264 (CCPA 1943). In the instant case, none of the active ingredients are applicants compounds. These biochemical property of these are linked to processes in cell cycle/division. From the combined teachings of one of skill in the art would have reasonable expectation of success in combining the agents for synergistic or additive effect. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ...[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
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(s) 31, 49-57 59-69 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.
Base claim 31 recites formulae and derivatives thereof for the ingredients.
The term ‘derivative’ in claim 31 render the scope of the claim vague and indefinite as it includes more than what is presented with the formulae, even though the variables of the formulae are defined. This is explained below:
For example, compound with the first options for R1 and R2 of formula I. It is unclear what derivative of the compound is intended here. Dependent claims do not solve the problem of the base claim 31.
Similarly, what derivatives of UMK57 (compound of dependent claim 50) intended here is unclear.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625
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Adaptive Resistance to an Inhibitor of Chromosomal Instability in Human Cancer Cells
By: Orr, Bernardo; Talje, Lama; Liu, Zhexian; Kwok, Benjamin H.; Compton, Duane A.
Cell Reports (2016), 17(7), 1755-1763 | Language: English, Database: CAplus and MEDLINE
Karyotype diversity is a hallmark of solid tumors that contributes to intratumor heterogeneity. This diversity is generated by persistent chromosome mis-segregation associated with chromosomal instability (CIN). CIN correlates with tumor relapse and is thought to promote drug resistance by creating a vast genomic landscape through which karyotypically unique clones survive lethal drug selection. We explore this proposition using a small mol. (UMK57) that suppresses chromosome mis-segregation in CIN cancer cells by potentiating the activity of the kinesin-13 protein MCAK. Sublethal doses of UMK57 destabilize kinetochore-microtubule (k-MT) attachments during mitosis to increase chromosome segregation fidelity. Surprisingly, chromosome mis-segregation rebounds in UMK57-treated cancer cells within a few days. This rapid relapse is driven by alterations in the Aurora B signaling pathway that hyper-stabilize k-MT attachments and is reversible following UMK57 removal. Thus, cancer cells display adaptive resistance to therapies targeting CIN through rapid and reversible changes to mitotic signaling networks.
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Janssen, Loss of Kif18A Results in Spindle Assembly Checkpoint Activation at Microtubule-Attached Kinetochores, Current Biology 28, 2685–2696, September 10, 2018.
Locke, Structural basis of human kinesin-8 functionand inhibition, PNAS | Published online October 23, 2017 | E9539–E9548BIOPHYSICS ANDCOMPUTATIONAL BIOLOGYPNAS PLUS