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 .
Priority
The instant application, filed 04/05/2024, is the national stage entry of PCT/US2022/046056, filed 10/07/2022, which claims priority to U.S. Provisional Patent Application No. 63/253,777, filed on 10/08/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55.
Information Disclosure Statement
The Information Disclosure Statement filed on 10/14/2024 is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statement has been considered.
Status of Claims
Claims 1-47 were originally presented on 04/05/2024. Applicant’s preliminary amendments to the claims, also received on 04/05/2024, are acknowledged and entered. Claims 3-8, 10, 19-23, 25-30, 32, 36-38, 41-42, 44, and 46-47 are canceled. Claims 2, 18, 24, 31, 33, 34, 35, 39, 40, 43 and 45 are amended.
Claims 1-2, 9, 11-18, 24, 31, 33-35, 39-40, 43, and 45 are pending.
Claim Objections
Claims 2, 18, 24, 31, 33, 34, 35, 39, 40, 43 and 45 objected to because of the following informalities:
The claims that are objected to all recite blurry and barely legible text. This appears due to Applicant presenting claim amendment in color (e.g., redlines), or in gray. When the color or gray amendments are scanned into the file wrapper, the resulting text is blurry and barely legible. For example, the examiner cannot easily read what is presently claimed in the instant claim 2 because of the blurry and barely legible text. See the amendments to the instant claim 2 below:
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Instant claim 2 amendments.
See MPEP 608.01, subsection I (“Legibility includes ability to be photocopied and scanned so that suitable reprints can be made and paper can be electronically reproduced by use of digital imaging and optical character recognition. This requires a high contrast, with black lines and a white background.”).
Therefore, Applicant is required to present its claims and claim amendments in legible text.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 (b)
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.
Claims 2, 11, 17, 18, 24, 31, 33, 34, 35, 39, 40, 43, and 45 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.
Regarding claims 2 and 24 the phrases "such as”, “can be”, and “may be” render the claim indefinite because it is unclear whether the limitation(s) following the phrase(s) are part of the claimed invention. Preferences are properly set forth in the Specification. See MPEP § 2173.05(d).
Further regarding claims 2 and 24, the parenthetical recitation of substitution patterns for certain variables is improper and renders the claim indefinite because it is unclear whether the parenthetical limitations are part of the claimed invention. See, e.g., instant claim 2, R1 variable:
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.
Further regarding claims 2 and 24, they recite certain drawn chemical structures in the recitation of the R2 variable. One of skill in the art would be unable to understand what compounds are presently claimed because it is unclear if the drawn chemical structures replace the entirety of the R2 variable, or if instead they replace the “alkyls” given that the drawn chemical structures follow the “wherein the alkyls” clause. See R2 variable below:
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The same issue is present in the R4 variable.
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Accordingly, claims 2 and 24 are rejected as indefinite.
Regarding claims 11 and 33, they recite the ALDHis “263646 (646)” and “264202 (202)”. One of skill in the art would not reasonably understand what is presently claimed in these methods because the chemical structure of the ALDHis “263646 (646)” and “264202 (202)” are never defined in the Specification, Figures, or Claims.
Accordingly, claims 11 and 33 are rejected as indefinite.
Regarding claim 17, it recites “administering to the patient an adjuvant therapy to the administration of the immune cell, an amount of an … ALDHi[] effective to reduce TREG activity in the patient.” The claim term “the immune cell” lacks antecedent basis. As a result, the scope of the claim is unclear because the entire “adjuvant therapy” depends upon the source and function of “the immune cell”, which is uncertain. See claim 17:
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Instant claim 17.
Claims 24, 31, 33, 34, 35, 39, 40, 43, and 45 fail to provide clarity to the source and function of “the immune cell” within the context of claim 17.
Accordingly, claims 17 and its dependent claims 24, 31, 33, 34, 35, 39, 40, 43, and 45 are rejected as indefinite.
In the interests of compact prosecution, the examiner will interpret claim 17 reciting administering to a patient 1) an immunotherapeutic agent, and 2) an ALDHi as an adjuvant therapy to the immunotherapeutic agent.
Regarding claim 18, first, the parenthetical recitation of specific named active pharmaceutical ingredients (“APIs”) for “the immunotherapeutic agent” is improper and renders the claim indefinite because it is unclear whether the parenthetical limitations “(e.g., …” are part of the claimed invention. Second, the phrase "such as” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. Preferences are properly set forth in the Specification. See MPEP § 2173.05(d). See instant claim 18:
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Instant claim 18.
Accordingly, claim 18 is rejected as indefinite.
Regarding claim 39, it depends on claim 17, presents additional antecedent basis issues in addition to “the immune cell” limitation of claim 17, and recites conditional statements without clarifying when the conditions are triggered. As a result, the metes and the bounds of the claim are unclear.
Placing claim 17 into the text of claim 39 as required by the claim is shown below. See combined claims 17 and 39 (text from claim 39 is underlined):
An immunotherapy method for increasing an immune response to a pathogen or cancer cell antigen in a patient, comprising:
administering to a patient an immunotherapeutic agent for increasing an antigen- specific immune response in a patient; and
administering to the patient an adjuvant therapy to the administration of the immune cell, an amount of an aldehyde dehydrogenase-lA enzyme inhibitor (ALDHi) effective to reduce TREG activity in the patient,
for treating cancer in a patient, comprising:
obtaining an antigen-presenting cell or a precursor thereof from the patient, wherein when an antigen-presenting cell precursor is obtained from the patient, further comprising culturing the precursor ex vivo in differentiation medium to differentiate the precursor to an antigen-presenting cell;
culturing the antigen-presenting cell in the presence of an antigen of a cancer cell from the patient to produce a matured antigen-presenting cell; and
administering the matured antigen-presenting cell to the patient with the ALDHi as an adjuvant therapy.
Combined claims 17 and 39 (text from claim 39 is underlined).
First, as shown above, there are now two patients. A/the patient recited in claim 17, and a/the patient recited in claim 39.
Second, as shown above, the claim recites the element “an antigen-presenting cell or a precursor thereof from the patient”, followed by a conditional statement, “wherein when an antigen-presenting cell precursor is obtained from the patient”. It is unclear if the second “an antigen-presenting cell precursor [] obtained [] from the patient” is the same “an antigen-presenting cell or a precursor thereof from the patient”, because 1) the second “precursor” lacks clear antecedent basis, and 2) there are multiple a/the “patient” elements recited in the claim. Moreover, it is unclear “when an antigen-presenting cell precursor is obtained from the patient” (emphasis added). The claim specifies no conditions for “when” this element occurs or is met.
Third, the claim continues to introduce another “an antigen-presenting cell” obtained from “further comprising culturing” an unclear “precursor”.
As a result of these issues, it is unclear which patient provides which cells and which precursors, when certain precursors are obtained, and what is ultimately done with each cell and each precursor with respect to the multiple patients recited.
Therefore, one of ordinary skill in the art would not be able to understand the metes and bounds of what is presently claimed, and claim 39 is rejected as indefinite.
Regarding claim 40, it depends on claim 39 and inherits its problems. It also recites
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Instant claim 40.
One of ordinary skill in the art would not be able to understand the metes and bounds of what is presently claimed in this method because the recitation of “a precursor thereof” has unclear antecedent basis given the numerous precursors recited in the claim. Moreover, it is unclear what triggers “optionally” obtaining “a bone marrow progenitor cell” from any of the patients recited. Further, it is unclear when this option occurs, if “the method comprises differentiating the bone marrow progenitor cell to a dendritic cell” ex vivo, or if Applicant intends the claim to read on the natural process of differentiation of bone marrow progenitor cells to dendritic cells in patients.
Therefore, claim 40 is rejected as indefinite.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 13 Anticipated by Chute 2006
Claims 1 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chute 2006.1
Instant claim 1 recites:
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Instant claim 1.
Instant claim 13 recites
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Instant claim 13.
Chute 2006 teaches at Title: “Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells”. Therefore, the subject matter of claim 1 was known.
Chute 2006 exemplifies the ALDHi diethylaminobenzaldehyde (“DEAB”), which reads on instant claims 1 and 13 (see also, Instant Specification at 30, stating DEAB is an embodiment of the instantly claimed invention):
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, from Instant Specification at 30
Chute 2006 teaches at Abstract that ALDHi administration expands HSCs. Bone marrow (“BM”) derived HSCs are exemplified throughout Chute 2006. See Chute 2006 at Abstract:
Aldehyde dehydrogenase (ALDH) is an enzyme that is expressed in the liver and is required for the conversion of retinol (vitamin A) to retinoic acids. ALDH is also highly enriched in hematopoietic stem cells (HSCs) and is considered a selectable marker of human HSCs, although its contribution to stem cell fate remains unknown. In this study, we demonstrate that ALDH is a key regulator of HSC differentiation. Inhibition of ALDH with diethylaminobenzaldehyde (DEAB) delayed the differentiation of human HSCs that otherwise occurred in response to cytokines. Moreover, short-term culture with DEAB caused a 3.4-fold expansion in the most primitive assayable human cells, the nonobese diabetic/severe combined immunodeficiency mouse repopulating cells, compared with day 0 CD34+CD38−lin− cells. The effects of DEAB on HSC differentiation could be reversed by the coadministration of the retinoic acid receptor agonist, all-trans-retinoic acid, suggesting that the ability of ALDH to generate retinoic acids is important in determining HSC fate. DEAB treatment also caused a decrease in retinoic acid receptor-mediated signaling within human HSCs, suggesting directly that inhibition of ALDH promotes HSC self-renewal via reduction of retinoic acid activity. Modulation of ALDH activity and retinoid signaling is a previously unrecognized and effective strategy to amplify human HSCs.
Chute 2006 at Abstract (emphases added).
See also, Chute 2006 at 11707, under Results:
The progeny of CB and BM CD34+CD38−lin− cells after 7 days of culture with DEAB + TSF contained significantly higher percentages of primitive CD34+CD38− cells compared with the day 7 progeny of TSF alone (Fig. 1b and Fig. 5a, which is published as supporting information on the PNAS web site; P = 0.02 and P = 0.01, respectively). DEAB + TSF cultures supported a mean 4-fold total cell expansion and a maintenance of absolute numbers of BM CD34+CD38− cells compared with day 0.
Chute 2006 at 11707 (emphasis added).
Chute 2006 at 11711-11712 explains the mechanism and its application in the clinic:
Improved characterization of the pathways that regulate HSC self-renewal will facilitate the development of therapies to amplify HSCs in vitro or in vivo for clinical purposes. In this study, we have characterized the novel contributions of the enzyme ALDH and retinoid signaling to human HSC differentiation and self-renewal. ALDHs are NAD(P)+-dependent enzymes that oxidize a large number of aldehydes to their corresponding carboxylic acids (17, 31). Several different ALDH isoforms (30) have been identified that are responsible for the metabolism of ethanol (34), catecholamines, (14) and the conversion of vitamin A to its active metabolite, retinoic acid (17). ALDH is also a selectable marker of human stem/progenitor cells (13, 15, 16). However, the contribution of ALDH activity to HSC function has remained unknown. In this study, we show that inhibition of ALDH activity with DEAB delayed the phenotypic and functional maturation of HSCs in response to thrombopoietin, SCF, and flt-3 ligand. ALDH inhibition, coupled with TSF, also gave rise to a 3.4-fold increase in SRCs in short-term culture, whereas treatment with TSF alone was associated with a 2-fold reduction in SRC content compared with input. Importantly, secondary transplant studies confirmed that long-term repopulating stem cells were maintained in cultures treated with DEAB. These studies indicate that ALDH plays a critical role in human HSC differentiation. Moreover, inhibition of ALDH, when combined with early acting cytokines, is sufficient to induce the amplification of human HSCs.
In light of the observed effects of ALDH inhibition on the amplification of human HSCs in culture, we also sought to determine the mechanism through which this effect occurred. Because ALDH1 is the predominant isoform within HSCs (11, 14, 32) and is the dominant isoform in mammals that regulates the conversion of retinaldehydes to retinoic acids (31), we tested whether DEAB specifically inhibited ALDH1 activity in HSCs and the effect this had on RAR-response genes. Our studies confirmed that DEAB treatment blocked the capacity for HSCs to convert retinaldehyde into retinoic acids by virtue of a marked decrease in expression of cEBPε, which is an RAR-specific response gene. Because ALDH1 is the dominant isoform required for the conversion of retinaldehyde to retinoic acids, these results also confirmed that the effect of DEAB on HSC differentiation was predominantly mediated through inhibition of ALDH1. Taken together, these data provide strong evidence that ALDH1 mediates the differentiation of HSCs via production of intracellular retinoic acids and that targeted inhibition of this enzyme promotes HSC self-renewal via inhibition of retinoic acid signaling.
The data presented here demonstrate that modulation of retinoid signaling can induce the expansion of human HSCs. There are several implications of these observations. First, the functional role of ALDH1 in HSC fate and the link between ALDH1 activity, retinoid signaling, and HSC self-renewal has not been previously described. Interestingly, Purton et al. (35, 36) reported that culture of murine c-kit+sca-1+lin− cells with ATRA for 14 days enhanced the maintenance of cells with in vivo repopulating capacity as compared with culture with cytokines alone. These results appear to contrast with our observations that inhibition of ALDH1 and retinoid signaling induces the expansion of human HSCs. These differences may be explained by differences in the contribution of ALDH1 activity to HSC fate between mice and humans or differences in the repopulating assays being performed. We have initiated additional studies to determine whether the function of ALDH1 in hematopoiesis is conserved in both humans and mice. Our data also suggest that cytokines, such as thrombopoietin, SCF, and flt-3 ligand, induce HSC differentiation via induction of retinoid signaling, perhaps mediated through increased ALDH1 activity. This hypothesis is supported by the recent observation that another cytokine, IL-3, induces hematopoietic progenitor cell differentiation via activation of Stat5 which, in turn, activates retinoid signaling (37). Our results also have implications for the development of strategies to amplify human HSCs for clinical purposes. We performed these studies on primary human HSCs, and our observations are therefore directly translatable to clinical protocols to expand human HSCs. Moreover, in contrast to other reported strategies to expand HSCs in vitro (5, 38), the approach we have described does not depend on the genetic modification of HSCs or coculture with surrogate stromal cell niches to achieve potency (39, 40). Finally, the observed in vivo multilineage differentiation of DEAB-treated HSCs transplanted in NOD/SCID mice demonstrates that ALDH inhibition does not significantly alter the normal differentiation program of human HSCs. It will be important to further augment the expansion of HSCs described here via the combination of ALDH inhibitors with other ligands capable of inhibiting HSC differentiation programs. In addition, it will also be important to directly modulate RAR and RXR signaling in primary HSCs. We have observed that a selective RXR modulator causes the enhancement of SRC content in short-term culture in a manner highly comparable to ALDH inhibition (J.P.C., D.P.M., G.G.M., and R.S., unpublished data).
In summary, our data suggest that ALDH1 functions fundamentally in HSCs to promote differentiation via the production of retinoic acids. The notion that ALDH1 is both a selectable marker of stem and progenitor cells (13, 14) and a critical regulator of stem cell differentiation appears counterintuitive. However, because a fundamental property of HSCs is the ongoing production of all mature hematopoietic cells, it is not surprising that HSCs would possess a differentiation program (e.g., ALDH1 activity, production of retinoic acids) that can be activated early in their lifespan, particularly in response to external stimuli (e.g., cytokines). Production of large numbers of HSCs lacking such an early differentiation capacity would also be potentially pathologic. Therefore, we believe it is consistent with normal hematopoiesis that HSCs might possess in vivo repopulating capacity while also carrying the critical capacity for fairly rapid differentiation in response to external signals. The results presented here demonstrate that inhibition of ALDH and retinoid activity is sufficient to induce the expansion of human HSCs.
Chute 2006 at 11711-11712 (emphases added).
As stated above, the methods of Chute 2006 utilized stem cells from bone marrow, indicated with the “BM” designation, and cord blood, indicated with the “CB” designation.
Accordingly, Chute 2006 teaches the methods presently claimed in at least claims 1 and 13. Therefore, claims 1 and 13 are anticipated by Chute 2006.
Claims 1 and 13 Anticipated by US’462
Claims 1 and 13 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US’462.2
See, e.g., US’462 at 6, claims 1-13. Claims 1-4, and 8 in particular reciting DEAB as the ALDHi, read on at least the instant claims 1 and 13:
1. A method of promoting expansion of stem cells or progenitor cells, said method comprising contacting said cells an inhibitor of aldehyde dehydrogenase (ALDH) under conditions such that said expansion is effected, wherein said compound is not AGN 194310.
2. The method according to claim 1 wherein cells are hematopoietic stem cells, neuronal stem cells or muscle stem cells.
3. The method according to claim 2 wherein said cells are human hematopoietic stem cells (HSCs).
4. The method according to claim 3 wherein said HSCs are obtained from bone marrow, umbilical cord blood or peripheral blood.
5. The method according to claim 1 wherein said cells are CD34+, Thy-1+, Lin- stem cells.
6. The method according to claim 1 further comprising contacting said cells with an amount of a hematopoietic growth factor sufficient to effect said expansion.
7. The method according to claim 6 wherein said growth factor is selected from the group consisting of thrombopoietin, SCF and flt-3 ligand.
8. The method according to claim 1 wherein said ALDH inhibitor is DEAB or metabolite thereof.
9. The method according to claim 8, wherein said method further comprises contacting said cells with TSF.
10. A method of identifying a compound that promotes expansion of stem cells or progenitor cells and inhibits differentiation of said cells, said method comprises assaying said compound for its ability to inhibit ALDH, wherein a compound that inhibits ALDH is a candidate compound for promoting expansion of said cells.
11. A method of treating a patient suffering from a disease or disorder associated with decreased levels of myeloid, erythroid, lymphoid or megakaryocyte cells comprising administering to said patient stem cells expanded ex vivo according to the method of claim 1 under conditions such that said treatment is effected.
12. The method according to claim 11 wherein said patient is suffering from leucopenia.
13. A method of accelerating hematopoietic recovery in a patient in need thereof comprising administering to said patient an inhibitor of ALDH in an amount sufficient to effect said acceleration.
US’462 at 6.
The methods work with ALDH inhibitors. DEAB was used as a non-limiting example. See US’462 at 2:
[0020] ALDH inhibitors suitable for use in accordance of the invention include, for example DEAB and metabolites thereof, as well as other known inhibitors such as those described in U.S. Pat. Nos. 5,624,910 and 6,255,497. The invention also includes methods of identifying ALDH inhibitors appropriate for use in effecting stem cell expansion. Candidate compounds can be screened for their ability to inhibit ALDH, particularly, ALDH-1 (e.g., specifically the ALDH-1 mediated metabolism of retinol to retinoic acid)), for their ability to block cytokine-induced differentiation of stem cells (e.g., HSCs) and/or for their ability to block stem cell differentiation by modulating HOXB4 expression/activity. The invention does not include the use of AGN 194310 (Prus et al, Leuk. Lymph. 45:1025 (2004)) in expanding stem cells or subpopulations thereof.
US’462 at 2.
See US’462 at 5 (bottom right)-6 paragraph [0043] (“ALDH inhibition, coupled with TSF, also gave rise to a 2-fold increase in SRCs and a 9- to 11-fold increase in human hematopoietic cell repopulation in vivo compared to either day 0 CD34+CD38-lin- cells or their progeny following culture with TSF alone.”) (emphasis added).
US’462 explains that the methods work in vivo, following ex vivo culturing of the BM cells with flt-3 ligand (TSF) and DEAB. See US’462 at 3 et seq., Examples & Results, and in particular the following paragraphs:
Below: US’462 at 3, paragraphs 32-33
Below: US’462 at 4-5, paragraph 41
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See also, US’462 at 4, paragraph 37:
… The progeny of BM and CB CD34+CD38-lin- cells following culture with DEAB+TSF contained significantly higher percentages of primitive CD34+CD38- cells compared to the progeny of TSF alone (FIGS. 1B and 1C, P=0.01, and P=0.02, respectively). DEAB+TSF cultures supported a mean 4-fold total cell expansion and a maintenance of absolute numbers of CD34+CD38- cells compared to day 0. … Morphologic examination of the progeny of DEAB+TSF cultures revealed a predominance of cells with high nuclear:cytoplasmic ratios and prominent nucleoli, whereas TSF-cultured progeny contained primarily bands and myelocytes, suggesting that DEAB treatment maintained more immature progenitors during culture (data not shown). Taken together, these results indicated that inhibition of ALDH activity impeded HSC differentiation in response to cytokines.
US’462 at 4, paragraph 37.
See also, US’462 at 1-2, paragraph 10 and associated Figures, that explain differentiation capacity is retained in the bone marrow transplants treated with an ALDHis:
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US’462 at 1-2.
US’462 at 2-3 further explains the application of stem cells expanded ex-vivo in cancer treatments, and that the expanded stem cells maintain normal differentiation capacity, see, e.g., US’462 at 2-3
[0021] The ALDH inhibitors of the invention, advantageously used in combination with TSF (or other appropriate cytokine combination), result in the amplification of pluripotent cells that maintain normal differentiation capacity.
[0022] Stem cells expanded ex-vivo using an ALDH inhibitor of the invention can be used in the treatment of various diseases, including those characterized by decreased levels of either myeloid, erythroid, lymphoid or megakaryocyte cells of the hematopoietic system. In addition, they can be used to cultivate mature myeloid and/or lymphoid cells. Among conditions susceptible to treatment with hematopoietic cells expanded in accordance with the invention is leucopenia induced, for example, by exposure to viruses or radiation, or as a side effect of cancer therapy. The expanded cells of the invention can also be useful in preventing or treating bone marrow suppression or hematopoietic deficiencies that occur in patients treated with a variety of drugs.
[0023] The dosage regimen involved in ex vivo expansion of stem cells and methods for treating the above-described conditions can be determined by one skilled in the art and can vary with the ALDH inhibitor, the patient and the effect sought.
[0024] In addition to the ex vivo expansion of stem cells for therapeutic purposes (i.e., cord blood transplantation) the ALDH inhibitors can be used as systemic therapeutics, for example, for treating patients undergoing chemotherapy and/or radiotherapy to accelerate their hematopoietic recovery, as well as other patients suffering from blood cell disorders/deficiencies, including anemias (e.g., sickle cell anemia).
US’462 at 2-3.
See also, US’462 at paragraph 45 (“These studies were performed on primary human HSCs and, therefore, the observations are directly translatable to clinical protocols to expand human HSCs.”).
Accordingly, at least claims 1 and 13 are anticipated by US’462.
Claims 17, 18, and 43 Anticipated by WO’383
Claims 17, 18, and 43 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO’383.3
Instant claims 17 and 18 recite:
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Instant claims 17 and 18.
WO’383 at 3-5 discloses ALDHis of various formulas, such as:
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See also, WO’383 at 3 (explaining that the compounds are ALDHis):
[0011] Accordingly, in various embodiments, the present disclosure provides novel compounds and pharmaceutical compositions, which are useful in inhibiting aldehyde dehydrogenase (Aldh, ALDH), and particularly ALDH isoform 1a3 (ALDH1a3) and/or ALDH isoform 1a2 (ALDH1a2), or inhibiting retinoid pathway….
WO’383 at 3.
An exemplified ALDHi is the compound designated 140, see WO’383 at 128:
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WO’383 at 128.
WO’383 at 12 teaches the administration of its ALDHis with an immune checkpoint inhibitor.
[0060] … Exemplary ALDH1a2 and/or ALDH1a3 inhibitors were also shown herein as effective in inhibiting tumor growth in vivo either as a single agent or in a synergistic combination treatment with an immune checkpoint inhibitor (anti-PD-1 antibody).
WO’383 at 12 (emphasis added).
WO’383 at 95-96 teaches other immunotherapy protocols, including combinations with the immunotherapeutic agents recited in instant claim 18:
[0306] … In some embodiments, the method further comprises administering to the subject an effective amount of an immunotherapy, such as an immune check point inhibitor. Suitable immunotherapy for the methods described herein is not particularly limited and can include any of those known in the art, which can include for example, anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, lambrolizumab, pidilizumab, BMS-936559, or AMP-224), anti-PD-L1 antibody (e.g., atezolizumab, durvalumab, avelumab, YW243.55.S70, MEDI-4736, MSB-0010718C, LY3300054, BMS-936559, MPDL3280A, or MDX-1105), IL-2, autologous T cell therapy, bispecific antibody therapy, anti-TGFβ antibody, a JAK/STAT inhibitor, or any combination thereof.
WO’383 at 95-96 (emphasis added).
See also, WO’383 at 241-243, claims 70-83, and note that the ALDHis of WO’383 are effective in inhibiting TREG cell formation, as explained in claims 76 and 82-83:
70. A method of treating a cancer in a subject in need thereof, wherein the cancer is unresponsive to one or more immunotherapy or the subject has developed resistance to one or more immunotherapy, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-52 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 53, and optionally administering to the subject an immunotherapy.
71. The method of claim 70, wherein the cancer is unresponsive to treatment with anti-PD-1 or anti-PD-Ll antibodies.
72. The method of claim 70, wherein the subject has developed resistance to anti-PD- 1 or anti-PD-L1 antibodies-based treatment.
73. The method of any one of claims 70-72, comprising administering to the subject an anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA4 antibody, IL-2, autologous T cell therapy, bispecific antibody therapy, anti-TGFβ antibody, a JAK/STAT inhibitor, or any combination thereof.
74. The method of any one of claims 70-73, wherein the cancer is a breast cancer, colorectal cancer, kidney cancer, ovarian cancer, gastric cancer, thyroid cancer, testicular cancer, cervical cancer, nasopharyngeal cancer, esophageal cancer, bile duct cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, blood cancer, brain cancer, liver cancer, mesothelioma, melanoma, sarcoma, gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and/or endometrial cancer.
75. A method of treating a disease or disorder associated with retinoid pathway activation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-52 or a pharmaceutical salt thereof, or the pharmaceutical composition of claim 53.
76. The method of claim 75, wherein the disease or disorder is associated with immune tolerance, induction of Treg cells and/or M2 macrophages, and/or effector T cell suppression.
77. The method of claim 75 or 76, wherein the disease or disorder is cancer.
78. The method of claim 77, wherein the cancer is a breast cancer, colorectal cancer, kidney cancer, ovarian cancer, gastric cancer, thyroid cancer, urothelial cancer, testicular cancer, cervical cancer, nasopharyngeal cancer, esophageal cancer, bile duct cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, blood cancer, brain cancer, liver cancer, mesothelioma, melanoma, hematologic cancer, sarcoma, gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and/or endometrial cancer.
79. The method of any one of claims 75-78, further comprising administering to the subject an immunotherapy (e.g., an immune checkpoint inhibitor).
80. The method of claim 79, wherein administering the immunotherapy comprises administering to the subject an anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA4 antibody, anti-LAG-3, anti-TIGIT, IL-2, autologous T cell therapy, bispecific antibody therapy, anti-TGFβ antibody, a JAK/STAT inhibitor, or any combination thereof.
82. A method of inhibiting Treg cell and/or M2 macrophage formation in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1-52 or a pharmaceutical salt thereof, or the pharmaceutical composition of claim 53.
83. The method of claim 82, wherein the subject is characterized as having a cancer unresponsive to one or more immunotherapy or the subject has developed resistance to one or more immunotherapy.
WO’383 at 241-243, claims 70-83.
Claim 79 for example teaches administration of an ALDHi effective to reduce TREG activity and an anti-PD-L1 antibody (e.g., atezolizumab).
Accordingly, claims 17 and 18 are anticipated by WO’383.
Regarding instant claim 43, it recites:
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Instant claim 43.
See WO’383 at 179, teaching administration of the ALDHi 140 with an anti-PD-1 antibody immunotherapy agent to a patient, wherein the ALDHi is administered to the patient on the same day as each instance of the immunotherapy, and optionally for from one to ten days after the immunotherapy:
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WO’383 at 179.
See also, WO’383 FIG. 14, at pdf page 267/272, and its caption in WO’383 at 11:
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WO’383 FIG. 14, at pdf page 267/272, and its caption in WO’383 at 11.
Accordingly, claim 43 is anticipated by WO’383.
Last, the examiner has already shown that instant claims 1 and 13 are anticipated by Chute 2006 and does not need to repeat the rejection here. It is worth noting that multiple references, including Chute 2006, are expressly incorporated into WO’383.
See WO’383 at 181:
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WO’383.
See also, WO’383 at 211-221, paragraph [0550], References. Citation 158 is to Chute 2006. Synergies between Treg depletion and immunotherapies were known. See, e.g., citation 139.
Claims 17, 18, and 43 Anticipated by US’678
Claims 17, 18, and 43 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US’678.4
See US’678 at Abstract:
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US’678 at Abstract.
US’678 at cols. 50-53, claims 1-16, teach an immunotherapy method for treating cancer comprising administering an ALDHi such as the compound designated KS100 shown at col. 13,
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in combination an immunotherapeutic agent, including the same named APIs recited in the instant claim 18. See, e.g., US’678 at cols. 50-53, claims 1 and 12-13:
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US’678 at cols. 50-53, claims 1 and 12-13.
The ALDHis are effective to reduce TREG activity in a patient. See US’678 at col. 4 (“FIG. 27. KS100+PD1 is effective in reducing Tregs cells.”), and Fig. 27:
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US’678 at Fig. 27.
See also, US’678 at cols. 19-22, teaching additional combination therapies. For example, beginning on col. 20, around line 10, and continuing down, see combinations with multiple immunotherapeutic agents specifically encompassed by the claims, such as dendritic cells, CAR T cells, and ex vivo expanded allogeneic natural killer cells:
Combination treatments can allow for reduced effective dosage and increased therapeutic index of the composition including KS100 of the present invention (or Formula II-IV) and the one or more additional therapeutic agents used in methods of the present invention.
Optionally, a method of treating a subject having cancer or at risk of having cancer further includes an adjunct anti-cancer treatment. An adjunct anti-cancer treatment can be administration of an anti-cancer agent.
…
An anti-cancer agent administered according to aspects of the present invention can be an anti-cancer immune therapeutic agent. Thus, methods according to aspects of the present disclosure include administration of: an anti-cancer immune therapeutic agent, and KS100, for treatment of cancer in a subject.
The term “anti-cancer immune therapeutic agent” as used herein refers to agents which activate or suppress a component of the immune system of a subject for treatment of cancer in the subject. An anti-cancer immune therapeutic agent can be a cell-based agent, such as natural killer cells (NK cells), cytotoxic T lymphocytes, lymphocytes, macrophages, dendritic cells, and the like. An “anti-cancer immune therapeutic agent” which is a cell-based agent can include modified cells, such as genetically-modified, chemically-modified, or biochemically-modified, immune cells. Alternatively, “an anti-cancer immune therapeutic agent” can be a small molecule, protein (such as, but not limited to, an antibody), peptide, saccharide, nucleic acid, or other non-cell based agent.
NK Cell-Based Anti-Cancer Immune Therapeutic Agents
…
Non-limiting examples of NK cell-based anti-cancer immune therapeutic agents include autologous NK cells, ex-vivo stimulated mbIL-21 allogeneic NK, ex vivo expanded allogeneic NK cells, and NK-92 (Neukoplast).
CAR-T Cell-Based Anti-Cancer Immune Therapeutic Agents
…
Non-Cell Based Anti-Cancer Immune Therapeutic Agents
Particular non-cell based anti-cancer immune therapeutic agents include, but are not limited to, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, lymphocyte-activation gene 3 (LAG3) antibodies, T-cell immunoglobulin and mucin domain-3 (TIM3) antibodies, OX-40 agonists, Glucocorticoid-induced TNFR-related (GITR), BRAF inhibitors, and immune checkpoint inhibitors.
…
US’678 at cols. 20-22.
Accordingly, claims 17-18 are anticipated by US’678.
Regarding claim 43, see US’678 at 50 and Fig. 25, teaching the immunotherapeutic method wherein the ALDHi is administered to the patient on the same day as each instance of the immunotherapy, and optionally for from one to ten days after the immunotherapy:
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Accordingly, claim 43 is anticipated by US’678.
Claims 17, 18, 31, 33, 34, and 35 Anticipated by US’577
Claims 17, 18, 31, 33, 34, and 35 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US’577.5
Here, the examiner interprets the method recited in claims 17 and 18 as follows:
First clause: reciting administering a tumor vaccine to a patient
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This interpretation is consistent with the following sections of the Specification:
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Specification at 2 and 20-21.
Second clause: reciting administering an ALDHi encompassed by those recited in claims 24, 31, and/or 33-35
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This interpretation is consistent with claims 24, 31, and/or 33-35.
US’577 at 1-2 teaches multiple ALDHis, such as
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(recited in claim 31, and encompassed by claim 35), and
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(recited in claims 31, 33, and 34).
US’577 at 3 teaches that these ALDHis were indicated for treating cancers, such as ovarian cancer. “[0010] The further embodiments, the present invention provides the use of any one of the aforementioned compounds in the treatment of ovarian cancer.” US’577 at col. 3.
US’577 at 11 teaches that numerous anticancer agents are suitable for use with the ALDHis of the invention, including adoptive immunotherapy and tumor vaccines.
[0113] A wide range of therapeutic agents find use with embodiments of the present invention. Any therapeutic agent that can be co-administered with the agents of embodiments of the present invention, or associated with the agents of the present invention is suitable for use in the methods of the present invention. Some embodiments of the present invention provide methods (therapeutic methods, research methods, drug screening methods) for administering a therapeutic compound of the present invention and at least one additional therapeutic agent (e.g., including, but not limited to, chemotherapeutic antineoplastics, antimicrobials, antivirals, antifungals, and anti-inflammatory agents) and/or therapeutic technique (e.g., surgical intervention, radiotherapies).
[0114] Various classes of antineoplastic (e.g., anticancer) agents are contemplated for use in certain embodiments of the present invention.…
[0115] In some embodiments, exemplary anticancer agents suitable for use in compositions and methods of the present invention include, but are not limited to: … 10) adoptive immunotherapy … 15) tumor vaccines….
US’577 at 11 (emphases added).
Therefore, US’577 teaches the administration of adoptive immunotherapy and/or tumor vaccines and ALDHis recited in claims 31 and 33-35.
Accordingly, claims 17, 18, 31, 33, 34, and 35 are anticipated by US’577.
Claims 17, 18, 24, 31, and 33 Anticipated by US’055
Claims 17, 18, 24, 31, and 33 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US’055.6
US’055 at 59, claim 35, teaches a kit for use in a method of treating cancer comprising administering compounds encompassed by instant claims 24, 31, and 33 and one or more anticancer agents. Specific APIs are recited in claim 12 of US’055. See, e.g., US’055 at claims 1, 12, 27, and 35:
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12. The compound of claim 1, wherein the compound is selected from: … 6-((3-fluorobenzyl)thio)-2-(oxetan-3-ylmethyl)-5-phenyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one …
27. A kit comprising a compound of claim 1, and instructions for administering said compound to a patient having a hyperproliferative disease, wherein said hyperproliferative disease is cancer, wherein the cancer is one or more of any type of cancer having cancer stem cell activity, any type of cancer having ALDH related cancer stem cell activity, and any type of cancer having elevated ALDH activity, ovarian cancer, and epithelial ovarian cancer, wherein the ALDH is ALDH1A1, ALDH1A2, ALDH1A3, and/or ALDH2.
35. The kit of claim 27, further comprising one or more anticancer agents.
US’055 at claims 1, 12, 27, and 35.
The compound named “6-((3-fluorobenzyl)thio)-2-(oxetan-3-ylmethyl)-5-phenyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one” in claim 12 of US’055 is the compound designated “258085”, recited in the instant claims 31 and 33. The compound “258085” is a compound encompassed by the formulas recited in instant claim 24. See, e.g., US’055 at 29, right column:
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US’055 at, paragraph 237, teaches that “A number of suitable anticancer agents are contemplated for use in the methods of the present invention. Indeed, the present invention contemplates, but is not limited to, administration of numerous anticancer agents such as: … adoptive immunotherapy agents … tumor vaccines….”
It follows that the kit of US’055 includes adoptive immunotherapy agents and/or tumor vaccines as the one or more anticancer agents.
Therefore, using the kit of US’055 with its instructions for a method of treating cancer comprising administering compounds encompassed by instant claims 24, 31, and 33 in combination with adoptive immunotherapy agents and/or tumor vaccines reads on the instant claims 17, 18, 24, 31, and 33.
Accordingly, claims 17, 18, 24, 31, and 33 are anticipated by US’055.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 9, 11 and 13 Obvious over US’462 in view of US’055 and Chute 2006
Claim(s) 1, 2, 9, 11 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’462 in view of US’055 and Chute 2006.
Previous discussions of US’462, US’055, and Chute 2006 in the preceding 102 sections are incorporated herein.
As discussed, US’462 teaches that ALDHis promote expansion of stem cells, including HSCs obtained from bone marrow. US’462 exemplifies the ALDHi DEAB, encompassed by the instant claim 13.
However, US’462 does not appear to expressly teach the chemical structures of certain ALDHis encompassed by the instant claims 2, 9, and 11.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in promoting the expansion of stem cells, including HSCs obtained from bone marrow, by administering ALDHis encompassed by the instant claims 2, 9, and 11, because US’055 teaches ALDHis of the following formulas,
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including the ALDHi designated 258085,
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The ALDHi designated 258085 reads on the ALDHis recited in instant claims 1, 2, 9, and 11.
Chute 2006 further details the mechanism by which ALDHis promote expansion of stem cells, including HSCs obtained from bone marrow.
Therefore, one of ordinary skill in the art at the time of filing would reasonably expect that the ALDHi designated 258085, and others explicitly taught in US’055, would promote the expansion of stem cells, including HSCs obtained from bone marrow.
Secondary considerations may provide evidence of obviousness or non-obviousness. From the simple examples of US’462 and Chute 2006, expansion of stem cells obtained from bone marrow using similar growth media and the ALDHi DEAB result in 3.4 fold (Chute 2006) to 9-11 fold expansion and repopulation of HSCs (US’462). Applicant’s best example, compound 673A (9 fold expansion), is directly in line with observations from US’462 and Chute 2006. Therefore, Applicant’s data provide evidence of obviousness.
See Instant Specification at 38 and instant FIG. 12, depicting Applicant’s results.
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Instant Specification at 38.
See Instant FIG. 12:
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Instant FIG. 12.
Accordingly, claims 1, 2, 9, 11 and 13 were obvious at the time of filing.
Claims 1 and 11-16 Obvious over US’462 in view of US’577 and Chute 2006
Claim(s) 1 and 11-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’462 in view of US’577 and Chute 2006.
Previous discussions of US’462, US’577, and Chute 2006 the preceding 102 sections are incorporated herein.
As discussed, US’462 teaches that ALDHis promote expansion of stem cells, including HSCs obtained from bone marrow. US’462 exemplifies the ALDHi DEAB, encompassed by the instant claim 13.
However, US’462 does not appear to expressly teach the chemical structures of certain ALDHis encompassed by the instant claims 11-16.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in promoting the expansion of stem cells, including HSCs obtained from bone marrow, by administering ALDHis encompassed by the instant claims 11-16, because US’577 at 1-2 teaches multiple ALDHis, such as
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(recited in claim 15, also encompassed by claim 13), and
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(recited in claims 11-12 and 15, also encompassed by claims 13-14).
Further, regarding the compound recited in the instant claim 16 (shown below), for which Applicant provided no data but claimed in its methods:
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US’577 at 20 teaches that compounds pertaining to the following general formulas are ALDHis:
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US’577 at 20.
In US’577, “a substituted version of the aforementioned groups” includes methoxy. See, e.g., claim 3 structures, exchanging chlorine for methoxy:
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and
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.
The compound recited in the instant claim 16,
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, is just “a substituted version of the aforementioned group” used in the following ALDHi also recited in claim 3 of US’577 (same chlorine for methoxy exchange).
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Chute 2006 further details the mechanism by which ALDHis promote expansion of stem cells, including HSCs obtained from bone marrow.
Therefore, one of ordinary skill in the art at the time of filing would reasonably expect that the ALDHi explicitly taught in US’577 and permitted “substituted version[s]” would promote the expansion of stem cells, including HSCs obtained from bone marrow.
Secondary considerations may provide evidence of obviousness or non-obviousness. From the simple examples of US’462 and Chute 2006, expansion of stem cells obtained from bone marrow using similar growth media and the ALDHi DEAB result in 3.4 fold (Chute 2006) to 9-11 fold expansion and repopulation of HSCs (US’462). Applicant’s best example, compound 673A (9 fold expansion), is directly in line with observations from US’462 and Chute 2006. Therefore, Applicant’s data provide evidence of obviousness.
See Instant Specification at 38 and instant FIG. 12, depicting Applicant’s results.
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Instant Specification at 38.
See Instant FIG. 12:
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Instant FIG. 12.
Accordingly, claims 1 and 11-16 were obvious at the time of filing.
Claims 17, 18, 43 and 45 Obvious over WO’383
Claim(s) 17-18, 43 and 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO’383.
Previous discussions WO’383 in the 102 section and entire rejections of claims 17-18 and 43 under 35 U.S.C. 102 as being anticipated by WO’383 are incorporated herein.
As discussed, WO’383 explicitly teaches the subject matter of claims 17-18 and 43.
Instant claim 45, however, recites that the treatment exemplified in WO’383 beings at or extends to 100 days after tumor inoculation. See instant claim 45:
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Instant claim 45.
It is unclear if WO’383 exemplified the method presently claimed in claim 45.
However, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in beginning or extending the treatment protocol of WO’383 at/to 100 days because the method as exemplified in WO’383 showed consistent, immediate, and significant reductions in tumor volume at 25 days, and there is no indication at all in WO’383 that the patients had to be pulled from treatment. Indeed, WO’383 states the treatment causes “tumor regression”.
See also, WO’383 FIG. 14, at pdf page 267/272, and its caption in WO’383 at 11:
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WO’383 FIG. 14, at pdf page 267/272, and its caption in WO’383 at 11.
Secondary considerations may provide evidence of obviousness or non-obviousness. From the example WO’383, the method as exemplified in WO’383 showed consistent, immediate, and significant reductions in tumor volume at 25 days. Applicant’s data, however, show inconsistency, and delayed and/or insignificant reduction in tumor volume all the way up to day 100. It is further unclear from Applicant’s data when the test mice were administered the ALDHi in combination with the immunotherapeutic agent, and when the tumors were inoculated. See Instant FIG. 8:
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Instant FIG. 8.
Applicant’s experiment is explained in Specification at 37-38, Example 2, shown below. From the experiment itself, it is not exactly clear when the test mice were administered the ALDHi in combination with the immunotherapeutic agent, nor when the tumors were inoculated.
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Specification at 37-38.
Therefore, Applicant’s data provide evidence of obviousness. The protocol appears to be no better than what was already known in the art at the time of filing.
Accordingly, claims 17, 18, 43 and 45 were obvious at the time of filing.
Claims 17, 18, 31, 33, 34, 35, 43, and 45 Obvious over WO’383 in view of US’577 and US’678
Claim(s) 17, 18, 31, 33, 34, 35, 43, and 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO’383 in view of US’577 and US’678.
Previous discussions WO’383, US’577, and US’678 in the 102 sections and entire rejections of the respective claims under 35 U.S.C. 102 are incorporated herein.
The previous rejections of claims 17-18, 43 and 45 under 35 U.S.C. 103 as being unpatentable over WO’383 is incorporated herein.
As discussed, WO’383 expressly teaches the subject matter of claims 17-18 and 43 and establishes that one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in obtaining the subject matter of the instant claim 45. WO’383 exemplified ALDHis of its general formulas, such as the compound it designated 140.
WO’383 does not appear to expressly teach the chemical structures of certain ALDHis encompassed by the instant claims.
However, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in using the ALDHis recited in the instant claims 31, 33, 34, 35, in the exact same methods as exemplified in WO’383, because
US’577 at 1-2 teaches multiple ALDHis, such as
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(recited in claims 31, 33, and 34).
US’678 further teaches the generality of the treatment protocol recited in the instant claims. Indeed, ALDHis of different chemical structures, such as the compound designated KS100, were known to be effective in the exact same therapeutic methods.
Accordingly, claims 17, 18, 31, 33, 34, 35, 43, and 45 were obvious at the time of filing.
Claims 17, 18, 24, 31, 33, 43, and 45 Obvious over WO’383 in view of US’055 and US’678
Claim(s) 17, 18, 24, 31, 33, 43, and 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO’383 in view of US’055 and US’678.
Previous discussions WO’383, US’055, and US’678 in the 102 sections and entire rejections of the respective claims under 35 U.S.C. 102 are incorporated herein.
The previous rejections of claims 17-18, 43 and 45 under 35 U.S.C. 103 as being unpatentable over WO’383 is incorporated herein.
As discussed, WO’383 expressly teaches the subject matter of claims 17-18 and 43 and establishes that one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in obtaining the subject matter of the instant claim 45. WO’383 exemplified ALDHis of its general formulas, such as the compound it designated 140.
WO’383 does not appear to expressly teach the chemical structures of certain ALDHis encompassed by the instant claims.
However, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in using the ALDHis recited in the instant claims 24, 31, and 33 in the exact same methods as exemplified in WO’383, because
US’055 teaches many ALDHis of the following general formulas, see, e.g., claim 1 at 56:
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US’055 further teaches the ALDHi named “6-((3-fluorobenzyl)thio)-2-(oxetan-3-ylmethyl)-5-phenyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one” in claim 12 of US’055. This compound is the compound designated “258085”, recited in the instant claims 31 and 33. The compound “258085” is a compound encompassed by the formulas recited in instant claim 24. See, e.g., US’055 at 29, right column:
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US’678 further teaches the generality of the treatment protocol recited in the instant claims. Indeed, ALDHis of different chemical structures, such as the compound designated KS100, were known to be effective in the exact same therapeutic methods.
Accordingly, claims 17, 18, 24, 31, 33, 43, and 45 were obvious at the time of filing.
Claims 17, 18, 39 and 40 Obvious over US’074 in view of US’577 and US’462
Claim(s) 17, 18, 39 and 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’0747 in view of US’577 and US’462.
Claim Interpretation
As discussed in the section regarding 112(b), claims 17, 39 and 40 are each indefinite.
Presumably, claim 17 recites administering to a patient
1) an immunotherapeutic agent, and
2) an ALDHi as an adjuvant therapy to the immunotherapeutic agent.
Claim 18 specifies that the immunotherapeutic agent can be an antigen-presenting cell (an “APC”), like a cancer stem cell – dendritic cell vaccine.
Claim 39, dependent upon claim 17, appears to require three steps (effectively, it appears to completely replace the first two steps of claim 17):
Obtaining an APC from a patient,
Culturing the APC with a cancer cell from the patient to produce a matured APC,
Administering the matured APC with the ALDHi as an adjuvant therapy.
Claim 40, dependent on claim 39, simply requires that the APC is a dendritic cell.
Placed together, claim 40 appears to recite a method that requires the following steps:
Obtaining a dendritic cell from a patient,
Culturing the dendritic cell with an antigen of a cancer cell from the patient to form a cancer stem cell – dendritic cell vaccine,
Administering the cancer stem cell – dendritic cell vaccine with the ALDHi as an adjuvant therapy for treating cancer.
US’074
US’074 teaches preparation of cancer stem cell – dendritic cell vaccines, abbreviated as “CSC-DC” vaccines, and their administration for treating cancer. For example, US’074 teaches the steps of:
Obtaining a dendritic cell from a patient,
Bone marrow-derived dendritic cells were obtained from the mice patients, and
Culturing the dendritic cell with an antigen of a cancer cell from the patient to form a cancer stem cell – dendritic cell vaccine,
Lysate of unsorted tumor cells, ALDHlow or ALDHhigh cells was added to DCs at a 1:3 cell equivalent ratio, which were incubated to yield the CSC-DC. D5 and SCC7 cancer lines exemplified.
See, e.g., US’074 beginning at col. 17, Example 1 “Combined Radiation and Cancer Stem Cell Vaccine Treatment”,
(45) Mice:
(46) Female C57BL/6 (B6) mice were used at the 7 weeks of age or older. The University of Michigan Laboratory of Animal Medicine approved all the animal protocols.
(47) Murine Tumors:
(48) D5 is a poorly immunogenic melanoma of spontaneous origin syngeneic to B6 mice.
(49) Tumor Models:
(50) The first model involves the treatment of established tumors using CSC-DC vaccine as an additional strategy to radiation therapy (RT). Day 5 sc D5 tumors were treated with localized RT with repeat treatments on day 6. Vaccine therapy commenced on day 7. This combination therapy was repeated twice with one week apart. The second model involved the treatment of micrometastatic disease. Vaccination was initiated 24 hours after sub-cutaneous (s.c.) inoculation of D5 tumor cells in B6 mice, with repeated the vaccination one week later.
(51) Vaccination:
(52) ALDHFLUOR+ and ALDHFLUOR− cells were isolated from cultured D5 cells. Bone marrow-derived dendritic cells (DCs) were cultured in IL-4 and GM-CSF and were pulsed with the lysate of ALDHFLUOR+ or ALDHFLUOR− cells to generate tumor lysate-pulsed DCs. Mice were vaccinated with DC vaccines subcutaneously.
US’074 beginning at col. 17, Example 1 (emphases added).
See also, US’074 beginning at col. 21, Example 2 “Combined Radiation and Cancer Stem Cell Vaccine Treatment”,
(71) Mice.
(72) Female C57BL/6 (B6) and C3H/HeNCr MTV (C3H) mice were purchased from Jackson lab and Charles River Laboratories, respectively.…
(73) Culture of Tumor Cells.
(74) D5 is a poorly immunogenic clone of the melanoma cell line B16 syngeneic to B6 mice, and was originally established by our laboratory. Squamous carcinoma cell line SCC7, a poorly immunogenic tumor, is syngeneic to C3H mice. The cell lines were grown in complete medium ….
(77) Preparation of Dendritic Cell (DC) Vaccine.
(78) To prepare tumor cell lysates, unsorted D5 or SCC7 tumor cells, sorted ALDEFLUOR+/ALDHhigh or ALDEFLUOR/ALDHlow cells were suspended at a concentration of 1 million cells in 1 ml complete culture medium. Cells were lysed by five rapid freeze-thaw cycles in 37° C. water bath and liquid nitrogen (49). After centrifugation, tumor cell lysates were collected and stored in liquid nitrogen for later use. Bone marrow-derived murine DCs were generated as described previously (49). Bone marrow cells from the mice were cultured in complete medium supplemented with 10 ng/mL IL-4 and 10 ng/mL GM-CSF at a concentration of 1×106 cells/ml. Fresh medium supplemented with GM-CSF and IL-4 was added on days 2 and 4. On day 5, DCs were harvested by gentle pipetting and enriched by Opti-Prep density gradient medium. Lysate of unsorted tumor cells, ALDHlow or ALDHhigh cells was added to DCs at a 1:3 cell equivalent ratio. The DCs were then incubated at 37° C. for 24 h with 5% CO.sub.2. After incubation, the unsorted tumor cell lysate-pulsed DCs (H-DC), ALDHlow lysate-pulsed DCs (ALDHlow-DC) or ALDHhigh lysate-pulsed DCs (ALDHhigh-DC, e.g. CSC-DC) will be used as vaccine as specified in the subsequent experiments. Each mouse was inoculated with 2 million DCs per vaccine.
(79) Tumor Growth and Treatment Protocols.
(80) In micrometastatic tumor model, B6 or C3H mice were inoculated subcutaneously with 2,500 D5 cells or 5,000 SCC7 cells respectively. The 1st vaccine was administered 24 hours after tumor inoculation for treatment, followed by a 2nd vaccine on day 8. Tumor-bearing C3H mice were administered with a 3rd vaccine on day 15. In the established tumor model, B6 or C3H mice were inoculated s.c. with 0.05 million D5 cells or 0.5 million SCC7 cells respectively on day 0. The mice were treated with localized radiation therapy (RT) on day 5 and day 6 followed by the 1st DC vaccine on day 7. The combined RT+vaccine treatment was repeated on day 12, 13, 14 and 19, 20, 21 respectively. Thus, the RT was delivered 6 times, which were on days 5, 6, 12, 13, 19 and 20 with a total dose of 51 Gy (8.5 Gy×6), while vaccines were administrated 3 times, 1 week apart, which were on days 7, 14 and 21. Each experimental group contained 5-8 mice. Tumor volumes were measured 3 times per week. The long and short diameters of tumor mass were measured and the tumor volume was calculated as: tumor volume=(width2*length)/2. Survival was monitored and recorded as the percentage of surviving mice after tumor inoculation.
US’074 beginning at col. 21, Example 2 (emphases added).
US’074 at col. 1 (starting around line 60) – col. 2 teaches the administration of a CSC-DC vaccine for treating cancer in combination with radiation therapy:
In some embodiments, the present invention provides methods of treating (and/or preventing) cancer in a subject (or in a subject suspected of having cancer) comprising: treating a subject with the combination of an effective amount of radiation therapy and administration of an effective amount of antigen presenting cells, such that at least some cancer cells in the subject are killed, wherein the antigen presenting cells have been exposed to cancer stem cells or at least an antigenic portion of the cancer stem cells. In certain embodiments, the antigen presenting cells comprise dendritic cells.
US’074 at cols. 1-2.
US’074 at col. 8 (starting around line 40) – col. 9 teaches combination therapies with an additional therapeutic agent including “chemotherapeutic antineoplastics” and “hematopoietic growth factors”:
In certain embodiments, an additional therapeutic agent is administered with the radiation therapy and the antigen presenting cells. Any therapeutic agent that can be co-administered with the agents of the present invention, or associated with the agents of the present invention is suitable for use in the methods of the present invention. Some embodiments of the present invention provide methods for administering least one additional therapeutic agent (e.g., including, but not limited to, chemotherapeutic antineoplastics, antimicrobials, antivirals, antifungals, and anti-inflammatory agents) and/or therapeutic technique (e.g., surgical intervention, radiotherapies).
Various classes of antineoplastic (e.g., anticancer) agents are contemplated for use in certain embodiments of the present invention.…
In some embodiments, exemplary anticancer agents suitable for use with the present invention include, but are not limited to: … 11) hematopoietic growth factors….
US’074 at cols. 8-10.
US’074 at col. 27 (beginning around line 15) teaches treating tumor cells with an ALDHi such as DEAB:
To provide direct evidence that CSC-DC vaccine can induce anti-CSC immunity targeting CSCs, the ALDHhigh cell enriched population was examined in the s.c tumors freshly harvested from mice subjected to the CSC-DC treatment, either by itself in the treatment of micrometastatic D5 model or in combination with RT in the treatment of established D5 model. The identification of the ALDHhigh population was performed by flow cytometry as previously described (31). Tumor cells incubated with ALDEFLUOR plus the ALDH inhibitor DEAB were used as control to set the gate. ALDEFLUOR assays were done using multiple mice from each group, and the results were displayed with SE (FIG. 21A). In addition, the tumor cells from multiple mice of each experimental group were mixed, and generated representative flow cytometric graphs to demonstrate the identification of the ALDHhigh populations in each group (FIG. 21B). As shown in FIG. 21A in the micrometastatic D5 model, CSC-DC vaccination significantly reduced the percentage of ALDHhigh populations compared with PBS, H-DC, or ALDHlow-DC treatment (P=0.0002, P=0.0002 and P=0.0029, respectively). Primary s.c. tumor harvested from CSC-DC treated mice were found to contain only 1.7% ALDHhigh cells, which was significantly less than that present in the primary s.c. tumors of PBS-treated mice (13.4%), H-DC-vaccinated mice (7.5%) or ALDHlow-DC vaccinated hosts (8.3%) respectively (FIG. 21B).
US’074 at col. 27.
US’074 at col. 24 (beginning around line 5) teaches adjuvant use of CSC-DCs:
The particular micrometastatic tumor model used in the above experiments has relevance in the design of future clinical trials because resection of primary tumor is associated with high rate of local relapse and death from recurrent disease (51, 52). It is now well-accepted that local disease relapse is due to the presence of residual CSCs after the primary tumor removal (53). Hence, DC vaccine approaches that target CSCs at a micrometasatic level may prevent the cancer from relapsing in the adjuvant setting. However, in patients with locally advanced cancers, radiation therapy (RT) and/or chemotherapy may be the only option which can be offered. Therefore, the therapeutic efficacy of CSC-DC vaccine in the treatment of established disease was examined.
US’074 at col. 24.
Accordingly, US’074 teaches
Obtaining a dendritic cell from a patient,
Culturing the dendritic cell with an antigen of a cancer cell from the patient to form a cancer stem cell – dendritic cell vaccine,
The treatment of cancer comprising administering the cancer stem cell – dendritic cell vaccine as an adjuvant to radiation therapy,
Combinations with other chemotherapeutic antineoplastics and hematopoietic growth factors, and
The treatment of cancer cells with the ALDHi DEAB.
US’074 does not appear to specifically teach that the ALDHi DEAB was a known chemotherapeutic antineoplastic agent and also a hematopoietic growth factor.
However, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in administering the ALDHi DEAB as a chemotherapeutic antineoplastic agent and a hematopoietic growth factor in the methods of US’074 because US’577 teaches that the ALDHi DEAB is a known chemotherapeutic antineoplastic agent useful in a method of treating cancer comprising administering DEAB and a tumor vaccine, and US’462 teaches that the ALDHi DEAB would reasonably act as a hematopoietic growth factor by promoting the expansion of dendritic stem cells derived from bone marrow, and that it was further useful in accelerating recovery from radiation therapy.
US’577
For example, see US’577 at 1, paragraph [0008] (discussing that the following embodiments are therapeutic agents against cancer stem cells), and at paragraph [0009], bottom right, stating that the ALDHi DEAB is an embodiment of the invention:
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US’577 at 1, paragraphs [0008]-[0009].
See also, US’577 at 20-21, claim 1 teaching a general formula encompassing the ALDHi DEAB, at claim 10 (teaching combination with known chemotherapeutic agents), and at claims 16-23 (teaching its indication for treating cancers, in particular cancer stem cells):
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US’577 at 20-21.
US’577 at 11 teaches that numerous anticancer agents are suitable for use with the ALDHis of the invention, including adoptive immunotherapy and tumor vaccines.
[0113] A wide range of therapeutic agents find use with embodiments of the present invention. Any therapeutic agent that can be co-administered with the agents of embodiments of the present invention, or associated with the agents of the present invention is suitable for use in the methods of the present invention. Some embodiments of the present invention provide methods (therapeutic methods, research methods, drug screening methods) for administering a therapeutic compound of the present invention and at least one additional therapeutic agent (e.g., including, but not limited to, chemotherapeutic antineoplastics, antimicrobials, antivirals, antifungals, and anti-inflammatory agents) and/or therapeutic technique (e.g., surgical intervention, radiotherapies).
[0114] Various classes of antineoplastic (e.g., anticancer) agents are contemplated for use in certain embodiments of the present invention.…
[0115] In some embodiments, exemplary anticancer agents suitable for use in compositions and methods of the present invention include, but are not limited to: … 10) adoptive immunotherapy … 15) tumor vaccines….
US’577 at 11 (emphases added).
US’462
For example, see US’462 at 6, claims 1-4, 8, and 13 (teaching that the ALDHi DEAB promotes expansion of stem cells or progenitor cells including those derived from bone marrow, and that its administration accelerates hematopoietic recovery in a patient in need):
1. A method of promoting expansion of stem cells or progenitor cells, said method comprising contacting said cells an inhibitor of aldehyde dehydrogenase (ALDH) under conditions such that said expansion is effected, wherein said compound is not AGN 194310.
2. The method according to claim 1 wherein cells are hematopoietic stem cells, neuronal stem cells or muscle stem cells.
3. The method according to claim 2 wherein said cells are human hematopoietic stem cells (HSCs).
4. The method according to claim 3 wherein said HSCs are obtained from bone marrow, umbilical cord blood or peripheral blood.
8. The method according to claim 1 wherein said ALDH inhibitor is DEAB or metabolite thereof.
13. A method of accelerating hematopoietic recovery in a patient in need thereof comprising administering to said patient an inhibitor of ALDH in an amount sufficient to effect said acceleration.
US’462 at 6.
See also, US’462 at 3 (teaching that the systemic use of ALDH inhibitors can speed hematopoietic recovery following radiation therapy):
[0024] In addition to the ex vivo expansion of stem cells for therapeutic purposes (i.e., cord blood transplantation) the ALDH inhibitors can be used as systemic therapeutics, for example, for treating patients undergoing chemotherapy and/or radiotherapy to accelerate their hematopoietic recovery, as well as other patients suffering from blood cell disorders/deficiencies, including anemias (e.g., sickle cell anemia).
US’462 at 3.
Claims 17, 18, 39 and 40 were obvious at the time of filing
Accordingly, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in:
Obtaining a dendritic cell from a patient,
Culturing the dendritic cell with an antigen of a cancer cell from the patient to form a cancer stem cell – dendritic cell vaccine,
Administering the cancer stem cell – dendritic cell vaccine with the ALDHi such as DEAB as an adjuvant therapy for treating cancer,
because US’074 taught how to prepare cancer stem cell – dendritic cell vaccines and indicated their use as an adjuvant to radiation therapy in combination with a chemotherapeutic antineoplastic agent and also a hematopoietic growth factor. While US’074 exemplified administering an ALDHi such as DEAB for treating cancer cells, US’577 explained that DEAB was a known chemotherapeutic antineoplastic agent able to be combined with tumor vaccines. Further, US’462
explained that the ALDHi DEAB would reasonably act as a hematopoietic growth factor by promoting the expansion of dendritic stem cells derived from bone marrow, and that it was further useful in accelerating recovery from radiation therapy.
Accordingly, claims 17, 18, 39, and 40 were obvious at the time of filing.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
NSDP to US’632 as evidenced by PubChem Nivolumab and Brahmer 2010
Claims 17-18, 31 and 33-35 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. US 9468632 B2, hereinafter “US’632”, as evidenced by PubChem Nivolumab8 and Brahmer 2010.9 Although the claims at issue are not identical, they are not patentably distinct from each other because
Instant claims 17-18 recite:
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Instant claims 17-18.
Instant claims 31 and 33-35 depend on claim 17 and recite compounds
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and effectively encompass ALDHIs of the following formula (shown from claim 14):
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see, e.g., claim 35:
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US’632 at claims 1-14 teach ALDHIs of the following formula:
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The ALDHis taught include 673A, see claim 12:
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US’632 teaches the combination of its ALDHis with known chemotherapeutic agents, see claim 7:
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US’632 at claim 7.
The chemotherapy agent nivolumab recited in the instant claim 18 was known prior to the filing of US’632, as evidenced by PubChem Nivolumab and Brahmer 2010. See PubChem Nivolumab at pdf page 2 of 43 (providing the synonym MDX-1106 for nivolumab), and Brahmer 2010 at 3167, Title and Abstract (reporting the Phase I study of MDX-1106).
Accordingly, claim 7 of US’632 teaches the administration of ALDHis encompassed by the instant claims 31 and 33-35 combined with a known chemotherapeutic agent. The instant claim 18 recites the administration of the same compounds with known chemotherapeutic agents, e.g. nivolumab. Accordingly, although the claims at issue are not identical, they are not patentably distinct from each other.
NSDP to US’632 in view of US’462
Claims 1 and 11-16 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. US 9468632 B2, i.e., US’632, in view of US’462.
The discussion of US’462 in the section regarding anticipation is incorporated herein.
Instant claim 1 recites:
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Instant claim 1.
Instant claims 11-16 recite ALDHIs of the following formula:
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Instant claim 14.
US’632 at claims 1-14 teach ALDHIs of the following formula:
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Yet, the claims of US’632 do not expressly teach that ALDHis promote the expansion of stem cells.
However, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in promoting the expansion of stem cells, including those obtained from bone-marrow, by using the ALDHis of US’632 because US’462 teaches that ALDHis promote the expansion of stem cells, including those obtained from bone-marrow.
See, e.g., US’462 at 6, claims 1-10:
1. A method of promoting expansion of stem cells or progenitor cells, said method comprising contacting said cells an inhibitor of aldehyde dehydrogenase (ALDH) under conditions such that said expansion is effected, wherein said compound is not AGN 194310.
2. The method according to claim 1 wherein cells are hematopoietic stem cells, neuronal stem cells or muscle stem cells.
3. The method according to claim 2 wherein said cells are human hematopoietic stem cells (HSCs).
4. The method according to claim 3 wherein said HSCs are obtained from bone marrow, umbilical cord blood or peripheral blood.
5. The method according to claim 1 wherein said cells are CD34+, Thy-1+, Lin- stem cells.
6. The method according to claim 1 further comprising contacting said cells with an amount of a hematopoietic growth factor sufficient to effect said expansion.
7. The method according to claim 6 wherein said growth factor is selected from the group consisting of thrombopoietin, SCF and flt-3 ligand.
8. The method according to claim 1 wherein said ALDH inhibitor is DEAB or metabolite thereof.
9. The method according to claim 8, wherein said method further comprises contacting said cells with TSF.
10. A method of identifying a compound that promotes expansion of stem cells or progenitor cells and inhibits differentiation of said cells, said method comprises assaying said compound for its ability to inhibit ALDH, wherein a compound that inhibits ALDH is a candidate compound for promoting expansion of said cells.
US’462 at 6, claims 1-10.
Accordingly, one of ordinary skill in the art at the time of filing, and in possession of the subject matter of US’632 claims 1-14, would have a reasonable expectation of success in using the ALDHis taught therein in the methods presently claimed in instant claims 1 and 11-16, because it was known that one could administer an ALDHi to promote the expansion of stem cells, including those obtained from bone-marrow.
Therefore, the subject matter of claims 1 and 11-16 was obvious over claims 1-14 of US’632 in view of US’462.
NSDP to US’626 in view of US’462
Claims 1, 2, 9, and 11 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. US 11944626 B2, hereinafter “US’626”, in view of US’462.
The discussion of US’462 in the section regarding anticipation is incorporated herein.
Instant claim 1 recites:
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Instant claim 1.
Instant claims 2, 9, and 11 recite ALDHis of the following formulas,
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US’626 at claim 1 teaches the following compounds of the same formulas:
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US’626 at claim 1.
The list of compounds taught in US’626 at claim 1 is the exact same as or significantly overlaps with the list recited in instant claim 9.
Claim interpretation is required to understand the utility of the compounds taught in US’626 at claim 1. See MPEP 804, subsection II, B.1.
See US’626 at Abstract (explaining that the compounds are ALDHis):
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US’626 at Abstract.
Yet, the claims of US’626 do not expressly teach that ALDHis promote the expansion of stem cells.
However, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in promoting the expansion of stem cells, including those obtained from bone-marrow, by using the ALDHis of US’626, because US’462 teaches that ALDHis promote the expansion of stem cells, including those obtained from bone-marrow.
See, e.g., US’462 at 6, claims 1-10:
1. A method of promoting expansion of stem cells or progenitor cells, said method comprising contacting said cells an inhibitor of aldehyde dehydrogenase (ALDH) under conditions such that said expansion is effected, wherein said compound is not AGN 194310.
2. The method according to claim 1 wherein cells are hematopoietic stem cells, neuronal stem cells or muscle stem cells.
3. The method according to claim 2 wherein said cells are human hematopoietic stem cells (HSCs).
4. The method according to claim 3 wherein said HSCs are obtained from bone marrow, umbilical cord blood or peripheral blood.
5. The method according to claim 1 wherein said cells are CD34+, Thy-1+, Lin- stem cells.
6. The method according to claim 1 further comprising contacting said cells with an amount of a hematopoietic growth factor sufficient to effect said expansion.
7. The method according to claim 6 wherein said growth factor is selected from the group consisting of thrombopoietin, SCF and flt-3 ligand.
8. The method according to claim 1 wherein said ALDH inhibitor is DEAB or metabolite thereof.
9. The method according to claim 8, wherein said method further comprises contacting said cells with TSF.
10. A method of identifying a compound that promotes expansion of stem cells or progenitor cells and inhibits differentiation of said cells, said method comprises assaying said compound for its ability to inhibit ALDH, wherein a compound that inhibits ALDH is a candidate compound for promoting expansion of said cells.
US’462 at 6, claims 1-10.
Accordingly, one of ordinary skill in the art at the time of filing, and in possession of the subject matter of US’626 claim 1, would have a reasonable expectation of success in using the ALDHis taught therein in the methods presently claimed in instant claims 1, 2, 9, and 11, because it was known that one could administer an ALDHi to promote the expansion of stem cells, including those obtained from bone-marrow.
Therefore, the subject matter of claims 1, 2, 9, and 11 was obvious over claim 1 of US’626 in view of US’462.
Prior Art Cited but not Applied
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Ghiaur, Gabriel, et al. "Regulation of human hematopoietic stem cell self-renewal by the microenvironment’s control of retinoic acid signaling." Proceedings of the National Academy of Sciences 110.40 (2013): 16121-16126.
Teaches expansion of BM stem cells using AGN194310.
Thacher Scott McNear et al., “THERAPEUTIC COMPOSITIONS CONTAINING RAR-ALPHA ANTAGONISTS”, International Publication No. WO 2017201200 A1, published 2017-11-23.
AGN194310 suppresses TREG formation.
Bazewicz, Christopher G., et al. "Aldehyde dehydrogenase in regulatory T‐cell development, immunity and cancer." Immunology 156.1 (2019): 47-55, hereinafter “Bazewicz 2019”.
Teaches that inhibiting ALDH inhibits TREG formation and impacts in oncology.
Hu, Yangyang, et al. "Therapeutic efficacy of cancer stem cell vaccines in the adjuvant setting." Cancer research 76.16 (2016): 4661-4672, hereinafter “Hu 2016”.
Teaches “adjuvant” use of dendritic cell-based cancer vaccines.
“Vaccination of mice with an ALDHhigh SCC7 CSC-DC vaccine after surgical excision of established SCC7 tumors reduced local tumor relapse and prolonged host survival. This effect was augmented significantly by simultaneous administration of anti-PD-L1, an immune checkpoint inhibitor.” Hu 2016 at Abstract.
Qiao Li, “ALDH1 ANTIGEN-PULSED DENDRITIC CELLS”, International Publication No. WO 2019136155 A1, published 2019-07-11.
Teaches updated protocol for preparing dendritic cell tumor vaccines.
Calmeiro, João, et al. "Dendritic cell vaccines for cancer immunotherapy: the role of human conventional type 1 dendritic cells." Pharmaceutics 12.2 (2020): 158.
Cited in IDS received 10/14/2024 as NPL cite 2, provides glossary of terms and highly relevant figures, see, e.g., Figure 1 at 4 and Table 1 at 9:
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Nwani, Nkechiyere G., et al. "A novel ALDH1A1 inhibitor targets cells with stem cell characteristics in ovarian cancer." Cancers 11.4 (2019): 502.
Teaches the ALDHi CM37 and its use in stem cells. Cites Chute 2006.
Pors, Klaus, and Jan S. Moreb. "Aldehyde dehydrogenases in cancer: an opportunity for biomarker and drug development?." Drug discovery today 19.12 (2014): 1953-1963.
Teaches that the Aldefluor™ assay contains the ALDHi DEAB.
Provides helpful figures, such as Figure 2:
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Liu, Liu, et al. "Synergistic killing effects of PD-L1-CAR T cells and colorectal cancer stem cell-dendritic cell vaccine-sensitized T cells in ALDH1-positive colorectal cancer stem cells." Journal of Cancer 12.22 (2021): 6629-6639.
Teaches synergies between CSC-DCs and PD-L1-CAR-T cells.
Teaches treatment with the ALDHi DEAB.
Ito, Fumito, et al. "Anti-CD137 monoclonal antibody administration augments the antitumor efficacy of dendritic cell-based vaccines." Cancer research 64.22 (2004): 8411-8419.
Protocol for preparing DC-CSCs, referenced in US’074
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christopher Evan Redwood whose telephone number is (571) 272-8882. The examiner can normally be reached Monday - Friday 6:15 AM - 4:45 PM.
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/C.E.R./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Chute, John P., et al. "Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells." Proceedings of the National Academy of Sciences 103.31 (2006): 11707-11712, hereinafter “Chute 2006”.
2 Chute, John P. “STEM CELLS”. U.S. Patent Application Publication No. US 20090220462 A1, published 2009-09-03, hereinafter “US’462”.
3 ESPOSITO; MARK, et al., “HETEROCYCLIC COMPOUNDS AND USES THEREOF”, International Publication No. WO 2022226383 A1, published 2022-10-27, priority to 2021-04-22, Applicants KAYOTHERA INC. and
TRUSTEES OF PRINCETON UNIVERSITY, hereinafter “WO’383”.
4 Robertson; Gavin P., et al., “Methods To Of Aldehyde Dehydrogenases For Treatment Of Cancer”, U.S. Patent No. US 12616678 B2, published 2026-05-05, priority to 2020-06-10, Assignee The Penn State Research Foundation, hereinafter “US’678”.
5 Buckanovich; Ronald, et al., “Methods And Compositions For Targeting Cancer Stem Cells”, U.S. Patent Application Publication No. US 20150297577 A1, published 2015-10-22, hereinafter “US’577”.
6 Larsen; Scott D., et al., “SMALL MOLECULE INHIBITORS OF ALDH AND USES THEREOF”, U.S. Patent Application Publication No. US 20190255055 A1, published 2019-08-22, hereinafter “US’055”.
7 Qiao Li, “CANCER STEM CELL VACCINATION AND TREATMENT”, U.S. Patent No. US 10173074 B2, published 2019-01-08, priority to 2012-10-24, hereinafter “US’074”.
8 PubChem record for Nivolumab, PubChem Reference Collection SID 481101762.
9 Brahmer, Julie R., et al. "Phase I study of single-agent anti–programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates." Journal of clinical oncology 28.19 (2010): 3167-3175, hereinafter “Brahmer 2010”.
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