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 .1
Status of Claims
Claims 1-7 and 9-19 are pending.
Election/Restrictions
Applicant’s election of the species in the reply filed on April 3 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The elected species are: (1) mitigation of clonal hematopoiesis associated with preventing/mitigating a hematological malignancy; and (2) a CDk46 inhibitor monotherapy, i.e. without chemotherapy.
Claims 4-6, and 9-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Because the species of CD4K4/6 monotherapy has been elected, claims 4-6 directed to combination with chemotherapy, are similarly withdrawn, along with claims 9-18. Claims 1-3, 7 and 19 are under examination.
Information Disclosure Statement
At this time, an information disclosure statement (IDS) has not been filed.
Claim Interpretation and Relevant Background Art
Claim 1 is broadly and reasonably interpreted to have a prevention aspect and mitigation aspect (equivalent to treatment) clonal hematopoiesis (mutant blood cells are propagated as cancer cells) to a patient in need when administered ANY CDK4/6 inhibitor, such as, Trilaciclib2 (aka G1T28), palbociclib3 or Ribociclib4 of claims 2-3. By preventing or mitigating clonal hematopoiesis, the invention treats or prevents hematological (blood) cancers (such as myeloid neoplasms, per claim 7), including myelodysplastic syndrome (MDS) and amyloid myeloid leukemia (AML) per claim 19.
Patel et al.5, while published in 2024, post priority date Oct 4 2022, provides background information on the first-in-class CDK4/6 inhibitor, Trilaciclib.6
Claim Objections
Claims 1 and 19 are objected to because of the following informalities:
Claim 1 recites in line 4 “clonal hematopoiesis.” As this is the second occurrence of the phrase “clonal hematopoiesis” in the claim, amendment of claim 1 to insert the term “the” before this second occurrence will overcome this objection.
Claim 19 recites “The method of claim 1, wherein the hematological cancer is selected from myelodysplastic syndrome (MOS) and acute myeloid leukemia (AML).” The term “cancer” is not used in claim 1, rather it recites a “hematological malignancy.” See last line of claim 1. Amendment of claim 1 and/or 19 to reconcile the two terms will overcome this objection.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 7 and 19 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 prevention and treatment of certain CDK 4/6 modulated cancers by inhibitors such as Trilaciclib, does not reasonably provide enablement for the full scope of treating ANY hematological malignancy/cancer/neoplasm with ANY CDK 4/6 inhibitor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set eight forth factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
The predictability or unpredictability of the art:
The instant claimed invention is highly unpredictable since one skilled in the art recognizes the mode of action of how cyclin-dependent kinase (CDK) 4/6 inhibitors rely on the presence of retinoblastoma protein to treat and/or prevent cancers, including the blood cancers as claimed.
Richter et al.7 teaches CDKs are involved in the regulation of cancer-initiating processes like cell cycle progression, transcription, and DNA repair; in hematological neoplasms, these enzymes are often overexpressed, resulting in increased cell proliferation and cancer progression. See abstract. Richter teaches while “[e]arly (pre-) clinical data using CDK inhibitors are promising, Richter cautions “identifying the right drug for each subgroup and patient is challenging.” See abstract.
Richter cautions “[t]o demonstrate their anti-leukemic potential, CDK4/6 inhibitors rely on expression of downstream signaling protein Rb [aka Retinoblastoma]. Intrinsic or acquired lack of Rb function results in resistance towards therapeutic CDK4/6 targeting.” See page 3, last paragraph. See also Figure 2, page 5, noting, intrinsic resistance to CDK inhibitors is driven by a lack of functional Rb protein; acquired resistance mechanism include Rb loss, that “may ultimately contribute to cell cycle progression and thus CDKI (cyclin-dependent kinase inhibitor) resistance.” Id. at Figure 2, page 5.
Thus, blood cancers (leukemia) without sufficient Rb capacity will be resistant to CDK inhibitors. Note, that per Boyer8, structural abnormalities of the RB gene (at 13q14) with absent [RB] protein expression is frequent in all types of human acute leukemia but are particularly common in acute myeloid leukemia with monocytic differentiation (M4 and M5). See section Epidemiology page 1 at bottom of page. Where Richter teaches the need for RB proteins to be present and expressed and Boyer teaches a particular species of AML (M4 and M5) to lack RB protein expression, the background notes that not all hematologic cancers are subject to treatment with CDK inhibitors.
Further, the Background of the Invention of the specification establishes that both MDS and AML are fatal diseases that are highly resistant to therapy. See page 1 of the specification. It is known that clonal hematopoiesis (CH) confers a risk of hematological malignancy/cancer, where CH clones will expand and acquire additional mutations, eventually leading to AML/MDS. Id. at Background of the Invention. However, it is clear from the background art of Richter and Boyer, not every version of MDS (a potential precursor to AML) and AML, is susceptible to CDK 4/6 inhibition as claimed. Therefore, the unpredictability of the art is a Wands factor against the full scope of enablement of the claimed invention.
The breadth of the claims
The instant claims are deemed very broad since these claims read on treatment of any hematological cancer with any CDK 4/6 inhibitor. The broad scope is a Wands factor against the enablement of the full scope of the claimed invention.
The amount of direction or guidance presented, and the presence or absence of working examples: It has been established that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” In re Fisher, 427 F.2d 833, 839 166 USPQ 18, 24 (CCPA 1970).
Starting at page 32 of the specification, Example 1 of the specification notes the genomic analysis of small lung cell cancer in patients receiving chemotherapy and the CDK4/6 inhibitor trilaciclib. Example 1 concludes a combination of chemotherapy and Trilaciclib is a promising approach to prevent the progression of clonal hematopoiesis (CH) to MDS. See page 35,lines 9-13.
Example 2 notes the impact of CDK 4/6 inhibition (Trilaciclib) on clonal hematopoiesis expansion in solid tumor patients receiving chemotherapy (i.e. mitigates CH expansion in solid tumor patients). Starting at page 35, lines 14-15.
Example 3 hypothesizes the impact of CDK 4/6 (Trilaciclib) inhibition on clonal hematopoiesis in murine models independent of chemotherapy. Example 3 proposes hypothetically the using palbociclib and ribociclib also. Note that the specification states experiments will be performed in murine models and various mice models. See pages 37-38.
It is noted that none of the working examples are a direct in vitro or in vivo model of treating a subject in need, with Trilaciclib let alone any and all CDK 4/6 inhibitors to prevent clonal hematopoiesis (CH) to prevent/mitigate hematological malignancies such as AML and MDS.
In summary, the unpredictability of the background of the art, the broad scope of claims and lack of working examples are Wands factors against enablement of the full scope of the claimed invention.
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 1-3, 7 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tiessen et al. First-in-human Phase 1 safety, PK, and PD study of the CDK4/6 inhibitor G1T28 [aka Trilaciclib] Meeting Abstract: 2015 ASCO Annual Meeting I J Clin Oncol 33, 2527(2015) Volume 33, Number 15.
Tiessen is cited by the Examiner on the PTO-892 form.
This novelty rejection solely address the prevention aspect of claims 1-3, 7 and 19, (i.e., to prevent blood cancers/myeloid neoplasms generally per claim 7, AML and MDS per claim 19), by administration of CDK4/6 inhibitors (i.e., Trilaciclib per claims 2-3). This property to prevent blood cancers generally, such as AML and MDS is inherent to the prior teaching of the administration of Trilaciclib to a subject in need, where all patients are in need of the prevention of blood cancers generally, such as AML and MDS.
Regarding claims 1-3, 7 and 19, Tiessen teaches the CDK 4/6 inhibitor Trilaciclib (therein identified as G1T28) was administered in a Phase I, where in Part 1 of the double blind, placebo controlled trial, subjects were randomized (3:1) to receive G1T28 or placebo as a single 30-minute IV infusion. See abstract. In Part 2, 8 subjects would receive single escalating oral doses of G1T28 (aka Trilaciclib) in three dosing periods. Id. As all patients are in need of the prevention of AML and MDS, Tiessen accordingly anticipates the rejected claims.
Claims 1-3, 7 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Stice et al. CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC Mol Cancer Res; 15(6) June 2017 pp 660-669.
Stice is cited by the Examiner on the PTO-892 form.
This novelty rejection solely address the prevention aspect of claims 1-3, 7 and 19, (i.e., to prevent blood cancers/myeloid neoplasms generally per claim 7, AML and MDS per claim 19), by administration of CDK4/6 inhibitors (i.e., Trilaciclib per claims 2-3). This property to prevent blood cancers generally, such as AML and MDS is inherent to the prior teaching of the administration of Trilaciclib to a subject in need, where all patients are in need of the prevention of blood cancers generally, such as AML and MDS.
Regarding claims 1-3, 7 and 19, Stice teaches the CDK 4/6 inhibitor Trilaciclib (therein identified as G1T28) was administered and evaluated in in vivo models as single agents. See abstract. Stice teaches the in vivo models were Male NSG mice subjects (see page 662, column 1 first paragraph), and dosed with G1T28 (aka Trilaciclib 100 mg/kg in citrate buffer). See page 662, column 1, Section Efficacy.
Note Stice also teaches the administration of another CDK 4/6 inhibitor, G1T38, aka Lerociclib, which anticipates the prevention of AML and MDS aspect of claims 1 and 19 with any CDK 4/6 inhibitor.
Claims 1-3, 7 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Weiss et al. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial Annals of Oncology 30: 1613–1621, 2019 Published online 27 August 2019.
Weiss is cited by the Examiner on the PTO-892 form.
This novelty rejection solely address the prevention aspect of claims 1-3, 7 and 19, (i.e., to prevent blood cancers/myeloid neoplasms generally per claim 7, AML and MDS per claim 19), by administration of CDK4/6 inhibitors (i.e., Trilaciclib per claims 2-3). This property to prevent blood cancers generally, such as AML and MDS is inherent to the prior teaching of the administration of Trilaciclib to a subject in need, where all patients are in need of the prevention of blood cancers generally, such as AML and MDS.
Note with regard to the elected species of CDK 4/6 inhibitor monotherapy, claim 1 is broadly and reasonably interpreted to include a monotherapy method, where the CDK 4/6 monotherapy is done prior to any subsequent chemotherapy in a subject in need of prevention of hematologic malignancies such as MDS and AML.
Regarding claims 1-3, 7 and 19, Weiss teaches subjects in in a phase Ib and phase II trial were administered Trilaciclib before etoposide/carboplatin (E/P) therapy on days 1-3 of each cycle. See Abstract, Section Patients and methods. As all patients are in need of the prevention of AML and MDS, Weiss accordingly anticipates the rejected claims.
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 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 1-3, 7 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Tiessen et al. First-in-human Phase 1 safety, PK, and PD study of the CDK4/6 inhibitor G1T28 [aka Trilaciclib] Meeting Abstract: 2015 ASCO Annual Meeting I J Clin Oncol 33, 2527(2015) Volume 33, Number 15 in view of Nebenfuehr et al. TheroleofCDK6incancer Int.J.Cancer.2020;147:2988–2995
Regarding claims 1-3, 7 and 19, Tiessen teaches the CDK 4/6 inhibitor Trilaciclib (therein identified as G1T28) was administered in a Phase I, where in Part 1, a double blind, placebo controlled trial, where subjects were randomized (3:1) to receive G1T28 or placebo as a single 30-minute IV infusion. See abstract. In Part 2, 8 subjects will receive single escalating oral doses of G1T28 (aka Trilaciclib) in three dosing periods. Id.
As required by the claims’ treatment aspect, it is noted that Tiessen does not teach the treatment of hematological malignancies, such as AML or MDS, known to be propagated by clonal hematopoiesis.
To address this, Nebenfuehr teaches the role of CDK 6 in hematologic malignancies. See Section 4, page 2991, columns 1-2. Nebenfuehr teaches CDK6 is critical in the progression of MLL-rearranged acute myeloid leukemia (AML). Id. Pharmacological inhibition of CDK6 by palbociclib unlocks blocked differentiation and reduces the leukemic phenotype in human AML cell lines. See Section 4, page 2991, column 1. Note that both palbociclib and Trilaciclib are known CDK 4/6 inhibitors and therefore it would be obvious to substitute one for another (MPEP 2144.05 obvious art recognized equivalent), in the treatment of AML and other CDK inhibitor susceptible hematologic cancers.
Prior to the filing of the present patent application, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) following the teachings of Tiessen of Trilaciclib as a CDK 4/6 inhibitor, modified by Nebenfuehr teachings in order to treat AML via CDK6 inhibition.
The PHOSITA would have a reasonable expectation of success Trilaciclib is a known CDK 4/6 inhibitor, where CDK 6 inhibition by palbociclib (MPEP 2144.05 obvious art recognized equivalent) is known to unlock blocked myeloid differentiation to reduce the leukemic phenotype in human AML cell lines.
Conclusion and Correspondence
In summary, no claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
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, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 CONTINUING DATA
This application has PRO 63/413,184 10/04/2022, it has published as US 2024/0108625.
2 Trilaciclib also known as 7′,8′-Dihydro-2′-[[5-(4-methyl-1-piperazinyl)-2-pyridinyl]amino]spiro[cyclohexane-1,9′(6′H)-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one (ACI)
2′-[[5-(4-Methylpiperazin-1-yl)pyridin-2-yl]amino}-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one
COSELATM
3 Palbociclib, also known as 6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one (ACI)
6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(1-piperazinyl)-2-pyridinyl)amino)pyrido[2,3-d]pyridin-7(8H)-one
6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]-8H-pyrido[2,3-d]pyrimidin-7-one
6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]pyrido[2,3-d]pyrimidin-7-one
Ibrance
Palbocyclib PD 0332991 PD 332991 PD 991
4 Ribociclib also known as -Cyclopentyl-N,N-dimethyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (ACI)
LEE 011 LEE 011A
5 Patel et al. A review of Trilaciclib, a first-in-class cyclin-dependent kinase 4/6 inhibitor, for the management of metastatic small-cell lung cancer Medicinal Chemistry Research (2024) 33:1757–1768
6 More specifically, Patel teaches the mechanism action of Trilaciclib, noting how it arrests the cell cycle, by inhibiting cyclin-dependent kinases 4 and 6, known to be crucial in driving cells from G1 to S phase. See page 1758, column 1. Patel suggests treatment of tumors that rely on CDK4/6 for their growth. See page 1758, column 2.
7 Richter et al. Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-) Clinical Application and Promising Approaches Cancers 2021, 13(10), 2497; https://doi.org/10.3390/cancers13102497
8 Boyer, Jacqueline “del(13a) in myeloid malignancies. Atlas of Genetics and Cytogentics in Oncology and Haematology webpage, Sep 1 2001. Accessed April 30 2026, https://atlasgeneticsoncology.org/haematological/1096/del(13q)-in-myeloid-malignancies.
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