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 .
Current Status of 18/476,247
Claims 1-9 have undergone amendments. Claim 10 has been cancelled. Thus, Claims 1-9, submitted on 26 May 2026, represent all claims currently under consideration.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Response to Arguments
Each of the objections for the use of “is characterized in that” is withdrawn. Applicant has replaced each instance with “wherein”.
The objection to Claim 10 is withdrawn. Applicant has cancelled the claim, rendering the objection moot.
The objections to Claims 3 and 7 are each withdrawn. Applicant has amended the claims to correct the informalities.
The 35 U.S.C. § 112(a) rejection of Claim 1 is withdrawn. Applicant has amended the claims to replace “prevention and/or treatment” with “treatment”.
The 35 U.S.C. § 112(b) rejections for the use of “preferably” are each withdrawn. Applicant has removed each instance of “preferably”.
The 35 U.S.C. § 112(b) rejections for lack of antecedent basis are each withdrawn. Applicant has corrected the lack of antecedent basis.
The 35 U.S.C. § 112(b) rejections of Claims 8 and 9 are each withdrawn. Applicant has deleted the narrow ranges, leaving only the broader ranges.
The 35 U.S.C. § 103 rejections of Claims 1-6 over Zhou in view of Yan, Imam, and El-Agamy as evidenced by Zhou, and Claims 7-10 over Zhou in view of Yan, Imam, El-Agamy, as evidenced by Zhou in further view of Peterson is maintained. Applicant argues that the prior art fails to teach or suggest the claimed method of treating anthracycline-induced cardiac damage with the specific alkaloid compound I. Applicant claims that there is no motivation found for the use of compound I for cardioprotection against anthracyclines found within either Zhou references, with Zhou demonstrating that the compound has anti-neuroinflammatory activity. Applicant claims that none of the prior art specifically establishes compound I as having any activity related to cardiac protection or anthracycline exposure, and there is no established predictable result that any compound with NF-kB inhibitory and antioxidant activity would mitigate anthracycline-induced cardiotoxicity, and that none of the cited references disclose or suggest that compound I would be safe and effective for the proposed use. The Examiner does not find these arguments to be persuasive. The Zhou references establish that Compound I is anti-inflammatory, and works by inhibiting activation of NF-kB, with Yan further demonstrating that this compound possesses good antioxidant activity. While Zhou and Yan fail to demonstrate that this compound is cardioprotective, Imam and El-Agamy both demonstrate with two different compounds that inhibition of oxidative stress and NF-kB signaling caused by doxorubicin (an anthracycline) helps to reduced caspase-3 activity, resulting in cardioprotection. Thus, it flows from the art of Zhou and Yan that, because Compound I inhibits inflammatory signaling via NF-kB, and possesses other anti-inflammatory and antioxidant properties, it will be useful in methods for the prevention of cardiotoxicity caused by anthracyclines in the treatment of cancer, as Imam and El-Agamy both demonstrate that inhibition of NF-kB is cardioprotective against damage by anthracyclines. Applicant further states that Zhou 2021 does not demonstrate that compound I inherently inhibits cleaved caspase-3 expression and activation of JNK, and in fact does not even mention compound I at all. The Examiner respectfully disagrees. Compound I is referred to in Zhou 2021 as “alk-A”, and is shown in Figure I (Page 2)
PNG
media_image1.png
232
459
media_image1.png
Greyscale
. Zhou states directly in the Abstract that “Alk-A and alk-B both inhibited ROS production, and suppressed cleaved-caspase-3 protein expression and the activation of JNK, as well as increasing ATP levels, favoring mitochondrial mitofusin protein expression, and relieving damage to mitochondrial DNA”. These data are further shown in Figure 4, demonstrating a concentration-dependent reduction in expression of cleaved-caspase-3. Section 2.4 further discusses the inhibition of JNK activation of by alk-A (“Compound I”) and alk-B.
Claim Objections
Claim 1 is objected to because of the following informalities: The phrasing “to patients when the patients are administered with anthracyclines” is confusing. The Examiner suggests amending the phrasing to “to patients when the patients are administered anthracyclines”. Appropriate correction is required.
Claim Rejections - 35 USC § 103- REJECTIONS MAINTAINED
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou (Phytochemistry Letters, 23, 2018, 57-61) in view of Yan (Journal of Agricultural and Food Chemistry, 2015, 63, 10611-10619), Imam (Pharmacological Reports, Volume 70, Issue 5, 5 October 2018, 993-1000), El-Agamy (Cancer Management and Research, Volume 11, 2019), as evidenced by Zhou (Molecules, 2021, 26, 1946).
Determining the Scope and Contents of the Prior Art:
Zhou (See IDS, 27 September 2023) discloses a new lignanamide and coumaroylamino glycoside, as well as eighteen compounds, including compound 15 (4-[(E)-p-coumaroylamino] butan-1-ol), which is alkaloid compound I of the examined application. The anti-inflammatory activity on LPS-induced BV2 microglia cells was evaluated. Compound 15 exhibited significant inhibitory effects on TNFα release from these cells (Abstract). Preliminary mechanism studies demonstrates that these compounds inhibit NF-kB signaling, which induces a large number of inflammatory activities, and coordinates with other inflammatory-related channels to trigger a variety of signal cascades, which together regulate the inflammatory response (Introduction). The authors state that the discovery of compounds that can regulate activation of NF-kB signaling is a path to treat disease.
Yan (See IDS, 27 September 2023) isolated several lignanmides from the hemp seed, including compound 7 (Figure 1), which is alkaloid compound I of the examined application. Lignanamide 7 exhibited good antioxidant activity, and may be a bioactive and protective compound (Abstract).
Zhou and Yan fail to demonstrate that inhibition of inflammatory response via NF-kB and antioxidant activity can be cardioprotective from anthracycline toxicity.
Imam investigated the influence on apremilast against doxorubicin-induced cardiotoxicity in Wistar rats. Oxidative stress, caspase-3 enzyme activity, gene expression, and protein expression were measured. The results demonstrate that administration of apremilast reversed doxorubicin-induced cardiotoxicity (Abstract). Doxorubicin enhances cytokine product such as TNFα and NF-kB (Introduction). Oxidative stress remains the leading cause of DOX-induced cardiotoxicity (Introduction). Reactive oxygen species production, increased inflammatory cytokines and MAPK signaling facilitates the activation of NF-kB transcription in myocardial tissue and apoptotic genes as well, and it is reported that NF-kB regulates DOX-induced apoptosis in many cancer cells/carcinomas (Introduction). Treatment with apremilast reduces caspase-3 enzyme activity (Figure 4). Apremilast decreases oxidative stress and protects the heart from oxidative stress mediated DOX-induced cardiotoxicity (Figures 1-3).
El-Agamy studied the impact of pristimerin on doxorubicin-induced cardiotoxic effects. Rats were treated with pristimerin before and 2 weeks concomitant with repeated doxorubicin injections. Pristimerin effectively alleviated doxorubicin-induced deleterious cardiac damage. The antioxidant activity of pristimerin was prominently through the amelioration of oxidative stress parameters and enhancement of antioxidants. Furthermore, pristimerin enhanced the activation of NrF2 signaling pathway and increased expression of antioxidant genes. Additionally, the anti-inflammatory effect of pristimerin was observed through the inhibition of MAPK and NF-kB signaling and subsequent inhibition of inflammatory mediators (Abstract).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
Zhou, Yan, Imam, and El-Agamy fail to specifically show that the compound claimed in the examined application can be used for cardioprotection from anthracyclines.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive training in medicine, with further training in cardiology and/or oncology, as well as pharmacology.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
Zhou, Yan, Imam, and El-Agamy are considered analogous to the claimed invention as all are involved in the study of the anti-inflammatory and anti-oxidant capacity of biologically active compounds. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to apply the claimed alkaloid compound for the treatment or prevention of anthracycline-induced cardiotoxicity as Zhou and Yan have demonstrated that this compound possesses both anti-inflammatory and anti-oxidant activity, and that the anti-inflammatory activity is mediated through inhibition of NF-kB, with Imam and El-Agamy demonstrating that different compounds which inhibit NF-kB and have antioxidant properties reduce or mitigate anthracycline-induced cardiotoxicity. The utilization of the claimed alkaloid compound in the prevention or treatment of anthracycline-induced cardiotoxicity is prima facie obvious combination of prior art elements according to known methods to yield predictable results (See MPEP § 2143 I (A)); the alkaloid compound of the examined application is known to possess both antioxidant and anti-inflammatory activity through inhibition of NF-kB, with Imam and El-Agamy demonstrating that different compounds which inhibit NF-kB and have antioxidant properties help to mitigate anthracycline-induced cardiotoxicity.
Regarding Claims 5 and 6, Zhou (2021) shows that the alkaloid compound of the invention inherently inhibits cleaved caspase-3 expression and the activation of JNK (Abstract). Thus, this is an inherent property of this compound.
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou (Phytochemistry Letters, 23, 2018, 57-61) in view of Yan (Journal of Agricultural and Food Chemistry, 2015, 63, 10611-10619), Imam (Pharmacological Reports, Volume 70, Issue 5, 5 October 2018, 993-1000), El-Agamy (Cancer Management and Research, Volume 11, 2019), as evidenced by Zhou (Molecules, 2021, 26, 1946) as applied to claims 1-6 above, and further in view of Peterson (WO 2013/176955; Publication Date: 28 November 2013).
Determining the Scope and Contents of the Prior Art:
The teachings of Zhou, Yan, Imam, El-Agamy, and Zhou are described previously and are fully incorporated into this rejection.
The cited references fail to teach the claimed compositions.
Peterson provides a method of reducing anthracycline-induced cardiotoxicity by administering a toxicity reducing compound to a patient receiving an anthracycline (Abstract). In certain embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin, such as doxorubicin (Page 5, Lines 5-7). In some embodiments, the toxicity reducing compound is administered simultaneously with the anthracycline (Page 16, Lines 11-13). In some embodiments, the toxicity-reducing compound has cardioprotective properties. In some embodiments, the cardioprotective properties of the compound can be characterized by the reduction of anthracycline-induced apoptosis in cardiomyocytes (Page 16, Lines 27-31). Toxicity reducing compounds may be provided in a pharmaceutical composition. Such a composition may also contain diluents, fillers, and other materials well known in the art (Page 21, Lines 13-16). Administration of toxicity reducing compounds used in the composition or to practice the methods of the present invention can be carried out in a variety of conventional ways, such as oral injection, inhalation, of injection (Page 22, Lines 20-23). When a therapeutically effective amount of a toxicity reducing compound is administered orally, the compounds may be in the form of a tablet, capsule, powder, solution, or elixir. When administered in a tablet form, the composition may additionally contain a solid carrier such as a gelatin or adjuvant. The tablet, capsule, and powder may contain from about 5 to 95% of a toxicity reducing compound (Page 22, Lines 24-29). When a therapeutically effective amount of a toxicity reducing compound is administered by injection, the compound may be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such acceptable solutions with regard to pH, isotonicity, stability and the like is within the art (Page 23, Lines 11-15). The amount of the toxicity-reducing compounds in the composition will depend upon the nature and severity of the cardiotoxicity, on the amount of anthracycline used, and on the nature of the prior treatments the patient has undergone. Ultimately, the practitioner will decide the amount of the toxicity reducing compound with which to treat an individual patient (Page 23, Lines 23-27).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The cited references fail to specifically show that the compound claimed in the examined application can be used for cardioprotection from anthracyclines.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive training in medicine, with further training in cardiology and/or oncology, as well as pharmacology.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The cited references and the claimed invention are considered analogous as all are involved in the study of the anti-inflammatory and anti-oxidant capacity of biologically active compounds. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to substitute the alkaloid compound of the examined application in place of the compounds of Peterson, and further use this compound and compositions comprising this compound for the treatment or prevention of anthracycline-induced cardiotoxicity. The prior art demonstrates that this compound has anti-inflammatory activity through inhibition of NF-kB, and also possesses anti-inflammatory activity, with Imam and El-Agamy showing that these mechanisms mitigate anthracycline-induced cardiotoxicity. Thus, it flows from the art which is cited that this compound would be useful in the methods disclosed by Peterson. Substituting this compound for the methods of Peterson is prima facie obvious combination of prior art elements according to known methods to yield predictable results (See MPEP § 2143 I (A)); the alkaloid compound of the examined application is known to possess both antioxidant and anti-inflammatory activity through inhibition of NF-kB, with Imam and El-Agamy demonstrating that different compounds which inhibit NF-kB and have antioxidant properties help to mitigate anthracycline-induced cardiotoxicity.
Regarding Claims 7-9, Peterson states that the compounds can be administered in the form of the claimed formulations, and that these compounds can be formulated in compositions known in the art. The claimed formulations are standard formulations within the art, and the artisan would be capable of arriving at these formulations through standard experimentation.
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou (Phytochemistry Letters, 23, 2018, 57-61) in view of Yan (Journal of Agricultural and Food Chemistry, 2015, 63, 10611-10619), Imam (Pharmacological Reports, Volume 70, Issue 5, 5 October 2018, 993-1000), El-Agamy (Cancer Management and Research, Volume 11, 2019), as evidenced by Zhou (Molecules, 2021, 26, 1946) as applied to claims 1-6 above, and further in view of Zhou (CN 112353810; Publication Date: 12 February 2021)
Determining the Scope and Contents of the Prior Art:
The teachings of Zhou, Yan, Imam, El-Agamy, and Zhou are described previously and are fully incorporated into this rejection.
The cited references fail to teach the claimed compositions.
Zhou claims the use of a compound for the treatment and/or prevention of cardiac injury resulting from anthracycline use, wherein the product reduces the expression of p-JNK and/or cleaved caspase-3. The toxicity reducing compound can be administered in dosage forms such as tablets, granules, capsules, suppositories, pills, solutions, and suspension, preferably tablets and solutions, and the solution is selected from injection solutions. Moreover, the tablets comprise 10-50 parts of the toxicity reducing compound, 100-200 parts lactose, 10-20 parts starch, 50-80 parts microcrystalline cellulose, 1-10 parts magnesium stearate, and 1-10 parts talc per 250 mg tablet. Solutions have 1-10 parts of toxicity reducing compound, 30-70 parts glucose, 6-12 parts sodium chloride, and 900-1000 parts water. (Claims 1-10).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The cited references fail to specifically show that the compound claimed in the examined application can be used for cardioprotection from anthracyclines.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive training in medicine, with further training in cardiology and/or oncology, as well as pharmacology.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The cited references and the claimed invention are considered analogous as all are involved in the study of the anti-inflammatory and anti-oxidant capacity of biologically active compounds. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to substitute the alkaloid compound of the examined application in place of the compounds of Zhou, and further use this compound and compositions comprising this compound for the treatment or prevention of anthracycline-induced cardiotoxicity. The prior art demonstrates that this compound has anti-inflammatory activity through inhibition of NF-kB, and also possesses anti-inflammatory activity, with Imam and El-Agamy showing that these mechanisms mitigate anthracycline-induced cardiotoxicity. Thus, it flows from the art which is cited that this compound would be useful in the methods disclosed by Zhou. Substituting this compound for the methods of Peterson is prima facie obvious combination of prior art elements according to known methods to yield predictable results (See MPEP § 2143 I (A)); the alkaloid compound of the examined application is known to possess both antioxidant and anti-inflammatory activity through inhibition of NF-kB, with Imam and El-Agamy demonstrating that different compounds which inhibit NF-kB and have antioxidant properties help to mitigate anthracycline-induced cardiotoxicity.
Regarding Claims 8 and 9, the compositions of Zhou and ratios of materials overlap with the ratios which are claimed in the examined application, rendering these compositions prima facie obvious due to overlapping, approaching, and similar ranges, amounts, and proportions (See MPEP § 2144.05 I).
Regarding Claim 9, the examined application claims the use of dextrose, with Zhou utilizing glucose. This substitution is prima facie obvious substitution of equivalents known for the same purpose (See MPEP 2144.06 II). These two compounds are known in the art to be standard reagents in the formulation of injectable formulations, and thus the artisan would not expect them to perform differently.
Conclusion
Claims 1-9 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/P.M.R./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
Prosecution Insights