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 .
Claims 1-10, submitted on 27 September 2023, 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.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The effective filing date is 29 March 2021.
Information Disclosure Statement
One Information Disclosure Statement (IDS), submitted 27 September 2023, is acknowledged and has been considered.
Claim Objections
Claims 2-10 are objected to because of the following informalities: Each claim is written stating “is characterized in that”. The Examiner finds this language difficult to interpret, and believes that these claims should be re-written to replace “is characterized in that” with “wherein”. Appropriate correction is required.
Claim 3 is objected to because of the following informalities: Claim 3 reads “further that stated anthracyclines…”. The Examiner believes the claim should be amended to read “wherein the anthracycline is selected from” to remove any clarity issues in interpreting the claim. Appropriate correction is required.
Claim 7 is objected to because of the following informalities: Claim 7 reads “further the stated solution is selected from injections”. The Examiner suggests amending the claim to “wherein the solution is selected from injections” to remove any clarity issues in interpreting the claim. Appropriate correction is required.
Claim 10 is objected to because of the following informalities: Claim 10 has a misspelling of “administration” (administeration). Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of cardiac damage, specifically due to chemotherapeutics such as anthracyclines, it does not reasonably provide enablement for prevention of cardiac damage. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth below:
The nature of the invention and breadth of the claims:
The claims are directed towards a method for the treatment and/or prevention of cardiac damage, such as the cardiac damage induced by chemotherapeutics such as anthracyclines comprising administering alkaloid compound I to a patient in need thereof. Thus, the methods are drawn to a method for the prevention of any form of cardiac damage, including those which are induced by chemotherapeutics.
The state of the prior art and the predictability or unpredictability of the art:
Qiu (Frontiers in Cardiovascular Medicine, December 2023) provides a review of anthracycline-induced cardiotoxicity, the mechanisms which underly toxicity, monitoring of this toxicity, and the current state of prevention of this toxicity. The use of anthracyclines is limited by dose-dependent cardiotoxicity which may emerge early within administration, or years after termination of therapy. A full understanding of the mechanisms of this toxicity has not been achieved, and is critical to the development of effective methods to protect against this form of cardiotoxicity and for early detection and treatment (Abstract). Although the mechanism underlying cardiotoxicity induced by anthracyclines is not well comprehended, proposed mechanisms include oxidative stress, alteration of cell death pathways, and alteration of epigenetics (3. Mechanism of anthracyclines-induced cardiotoxicity). Evident growth of oxidative stress is observed when the total dose of doxorubicin surpasses 500 mg/m2. Nitric oxide generated by catalyzation of nitric oxide synthase is a primary reason for anthracycline-mediated oxidative stress. Nitric oxide levels have been proved elevated in cardiotoxicity associated with anthracycline administration. Anthracyclines, by binding to eNOS reductase, boost semiquinone radical generation which reduces the free oxygen into superoxide free radicals. An imbalance between superoxide free radicals and NO levels is produced following binding of anthracyclines to eNOS reductase. Neilan et al. verified the important effect of eNOS on doxorubicin-mediated oxidative stress by eNOS knockout mice which exhibited low-level ROS and preserved myocardial function after treatment with doxorubicin (3.1.1 Effect of nitric oxide synthase on ROS production). Other proposed oxidative stress mechanisms include mitochondrial injury due to intercalation with mitochondrial DNA, leading to nucleoid aggregation and DNA reduction (3.1.3 Effect of mitochondrial injury on ROS production), dysregulation of intracellular calcium, causing cardiac tissue damage (3.1.4 Intracellular calcium dysregulation), and the formation of iron complexes causing oxidative stress and mitochondrial dysfunction (3.1.5. Fe-anthracycline complex).Alteration of cell death pathways, such as induction of autophagy resulting in cardiac death, induction of pyroptosis, and induction of apoptosis due to the prevalent oxidative stress, are further proposed mechanisms of injury. Finally, DNA methylation, histone modifications, and overexpression of various micro-RNAs are proposed epigenetic mechanisms for anthracycline induced cardiotoxicity. The current state of preventive strategies includes alteration of the dosing of the anthracycline by altering infusion times, limited lifetime doses, and the application of liposome-encapsulated anthracyclines, the use of the iron chelator dexrazoxane to limit ROS generation, use of statins due to their general cardioprotective benefits, and the use of ACE inhibitors, angiotensin receptor blockers, and beta blockers. However, the data for the pharmacological interventions are inconclusive and require further study to determine their efficacy in preventing cardiotoxicity induced by anthracyclines. The quality of evidence for the use of dexrazoxane is low, and further randomized trials are necessary before implementation of this therapy in clinical practice. Previous studies for the use of statins provide some evidence supporting their use, however, current research is not adequate to recommend statins for the prevention of anthracycline-induced cardiotoxicity, with further studies required to determine whether there is a clear role of statins in preventing this toxicity. RAS inhibitors may show some promise, but require to be further confirmed in larger randomized trials with great emphasis on clinically relevant end points, and longer follow-ups are essential to accurately determine the degree of cardiotoxicity prevention realized by ACEIs/ARB. Larger studies are also demanded to confirm the clinical relevance for the use of beta blockers and ACEIs for the prevention of anthracycline-induced cardiotoxicity (5. Prevention). The authors conclude by stating that early detection and long-term follow-up of anthracycline-induced cardiotoxicity via monitor means may enable intervention at an earlier stage. Prevention measures have not been fully verified, with larger clinical trials being necessary to achieve better understanding and prevention of anthracycline-induced cardiotoxicity. Moreover, the mechanism of anthracycline-induced cardiotoxicity should be explored further to identify methods for better preventing this toxicity (6. Conclusion). Thus, the current state of the art does not have a consensus on if this cardiotoxicity can be prevented, due to the lack of clinical evidence as well as the lack of understanding of the mechanism which underlies this toxicity.
The relative skill of those in the art:
The artisan would generally have an advanced degree in medicine, and further training in cardiology and oncology. However, their extensive training would not be sufficient to overcome the lack of evidence in both the prior art and found within the specification demonstrating that alkaloid compound I can be used to prevent any form of cardiac damage, and the evidence that cardiac damage induced by chemotherapeutics such as anthracyclines can be prevented in general.
The amount of direction or guidance presented and the presence or absence of working examples:
The specification provides figures which show that the alkaloid compound of the invention is capable of reducing apoptosis in vitro in a cardiomyocyte cell line, and can reduce the levels of cleaved caspase 3 as well as the expression of p-JNK, which demonstrates the treatment of cardiotoxicity induced by anthracyclines. However, the data presented in the specification is merely in vitro data, and there is no demonstration of the prevention of all forms of cardiotoxicity, nor is there any demonstration of the prevention of cardiotoxicity induced by anthracyclines specifically.
The quantity of experimentation necessary:
Considering the state of the art as described above, in particular with regards to the lack of evidence for the use of any compounds for the prevention of cardiac damage induced by anthracyclines, let alone a compound capable of preventing any form of cardiac damage, and the high unpredictability of the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate with the scope of the claims.
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 1-9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1 is directed to a method of prevention and/or treatment for cardiac damage. It is unclear how one can both prevent and treat a condition at the same time, as this is not possible. Not withstanding the 112(a) issue related to the prevention of cardiac damage caused by chemotherapy, the statement “and/or” raises a 112(b) issue. The Examiner suggests amending to “or treatment” to overcome this rejection. Claims 2-9 are similarly rejected as indefinite for depending on an indefinite claim without resolving the underlying issue of indefiniteness.
Claim 3 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Regarding claim 3, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 4-7 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claims 4 and 5 recite the limitation "the stated products" in Line 1. There is insufficient antecedent basis for this limitation in the claim, and it is unclear what “the stated products” encompasses.
Claim 7 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Regarding claim 7, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 7 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 7 recites the limitation "the dosage form" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 8 recites the limitation "the raw materials" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 8 recites the broad recitation “: 5-20 parts of compound I, 100-200 parts of lactose, 10-25 parts of starch, 50-80 parts of microcrystalline cellulose, 1-10 parts of magnesium stearate, and 1-10 parts of talcum powder”, and the claim also recites “10 parts of compound I, 150 parts of lactose, 15 parts of starch, 65 parts of microcrystalline cellulose, 5 parts of magnesium stearate, and 5 parts of talc” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 9 recites the broad recitation “0.2-1 part of compound I, 30-70 parts of dextrose, 6-12 parts of sodium chloride, and 900-1000 parts of water”, and the claim also recites “0.5 parts of compound I, 50 parts of dextrose, 9 parts of sodium chloride, and 940.5 parts of water” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 10 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 10 is indefinite because there is no gerund (“-ing” ending verb) to set out the steps of a method claim.
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 1-6 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).
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).
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 7-10 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).
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, and fails to teach an anti-tumor method involving the simultaneous administration of a toxicity reducing compound and anthracycline.
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).
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 7-10 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)
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, and fails to teach an anti-tumor method involving the simultaneous administration of a toxicity reducing compound and anthracycline.
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).
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.
Regarding Claim 10, Zhou does not explicitly claim an antitumor method involving the simultaneous administration of the anti-toxicity compound and anthracycline to a patient. However, it flows from the art of Zhou that the anti-toxicity compound and the anthracycline can be administered together, and the artisan would be motivated to administer these compounds simultaneously in order to maximize the reduction of toxicity and improve outcomes for the patient.
Conclusion
Claims 1-10 are rejected.
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/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625