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 .
DETAILED ACTION
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 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.
Status of the claims
Claims 1-2, 4-7 and 10 are examined on merits in this office action.
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 of this title, 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.
Claims 1-2, 4-7 and 10 are rejected under 35 U.S.C. 103 as obvious over Shchepinov (WO2020/102596A1) in view Rosell et al (Antioxidants 2019), Schacky (Nutrients 2021) and Everson et al (US 8,613,904 B2).
Shchepinov deuterated polyunsaturated fatty acid (PUFA) compounds for reducing lipid autooxidation and treatment of neurological or retinal diseases and conditions (Abstract and para [0001]). Shchepinov teaches the PUFA oxidation is a hallmark of many disease states (para [000]) and thus, there is a need for oxidation resistant PEFAs, that are useful for stabilizing polyunsaturated substances in patients, particularly having oxidation-related disorders or subjected to undesirable oxidative stress (para [0007]). Shchepinov discloses deuterated PUFA including deuterated docosahexaenoic acid (DHA) {compound of Formula (I) and para [0039]}. Shchepinov teaches that deuterated PUFA have a much stronger oxidation preventative effect (para [0032] and [0089]) and also teaches the compounds for treatment by administering (para [0017]). Shchepinov teaches administering deuterated DHA (D-DHA) orally as ethyl ester at different time periods for treatment of retina. Shchepinov teaches that D-DHA is delivered to retinal tissue via the blood stream and reaches effective doses above 1% after three days of dosing (para [0183]).
Shchepinov teach periodically administering deuterated PUFA including D-DHA but does not teach detection/accessing the amount of D-DHA in blood sample for monitoring uptake in blood.
Rosell teaches that bis-allylic deuterated DHA alleviates oxidative stress in retinal epithelial cells (Title). Rosell teaches that oxidative stress plays a crucial role in developing and accelerating retinal diseases including age-related macular degeneration (AMD) and docosahexaenoic acid (DHA), the main lipid constituent of retinal epithelial cell membranes, is highly prone to radical and enzymatic oxidation leading to deleterious or beneficial metabolites for retinal tissue. Rosell discloses deuterated DHA analog having deuterium selectively introduced at bis-allylic positions C-6 and C9 (Scheme 2, page 3) and teaches that the deuterated analog shows normal incorporation and assimilation in animals after oral supplements (abstract and Introduction; pages 2-4) and suggest the deuterated-DHA for macular degeneration treatment (page 4). Rosell teaches that high prevalence of DHA in retinal tissue indicates that DHA is effectively transferred from blood to retina (page 3, 2nd para).
Schacky teaches importance of determining blood level of DHA as the dietary intake of EPA and DHA (oral administration) does not correlate with the bioavailability for brain because of variability of adsorption during digestion. Schacky teaches that blood levels of EPA and DHA to clinical events or parameters usually found stronger correlations than those assessing dietary intake (pages 2-3).
Everson discloses a method for monitoring a patient for uptake of a compound (Cholate) utilizing isotopic analog of the compound for distinguishing from naturally present compound, wherein said method comprises: administering to said patient an effective dose of a isotopic compound (col 3 In 25-27); obtaining one or more blood samples from said patient after the start of oral administration (Abstract and claims 1-28). Everson teaches in one example, blood samples for measurement of cholate isotopes can be obtained at a baseline and several times after the baseline, for example, sample may be taken at 5, 10, 15, 20, 30, 45, 60, 75,90, 105, 120, 150, and less than 180 minutes post-dose where a total of 14 blood samples may be collected over 180 minutes (col. 7, lines 34-50; col. 11, lines 50-62). Everson teaches utilizing deuterated isotope of caffeine (D3 and D9) as test compound for quantitative assessment in serum over a concentration ranges after oral dosing with 300 mg caffeine (Col. 31). assessing the amount of a deuterated compound in said sample relative to the total amount of a non-deuterated compound (col 30 In 52 to col. 31, line 20 and claims 21-28). Everson teaches utilizing standard curve (col. 15; col. 26, lines 63-64).
Therefore, given the fact that Shchepinov teaches deuterated PUFA for treatment of neurological or retinal diseases by reducing lipid autooxidation (Shchepinov) and both Shchepinov and Rosell teach deuterated-DHA for treatment of macular degeneration and administering deuterated DHA (D-DHA) orally, and given the fact that Schacky teaches importance of determining blood level of DHA, which provides stronger correlation than those assessing dietary intake, it would be obvious to one of ordinary skilled in the art to envisage monitoring the deuterated DHA in blood of the orally administered D-DHA to access bioavailability of the D-DHA for retina with a reasonable expectation of success because Rosell teaches DHA is effectively transferred from blood to retina and Shchepinov teaches D-DHA is delivered to retinal tissue via the blood stream. From the description in mind of Everson, one of ordinary skilled in the art would readily understand that monitory blood level of deuterated DHA would involve periodically administering an effective dose of D-DHA, obtaining blood sample, accessing the amount of D-DHA in the sample relative to the total amount of DHA and incorporating comparing against a standard concentration curve based on specific dose of D-DHA in the assessment because the process of monitoring deuterated compound in blood has been disclosed by Everson.
In regards to claim 2, Everson discloses wherein the blood component being assessed is plasma (col 6 In 2-4 - ' ... plasma clearance of oral and intravenous cholic acid in subjects with and without chronic liver disease were studied ... '; col 11 In 54-57 - ' ... In one example, blood samples for measurement of chelate isotopes can be obtained at baseline and 5, 10, 15, 20, 30, 45, 60, 75,90, 105, 120, 150, and less than 180 minutes post-dose .. .') and assessing the amount of D-DHA in plasma would be obvious in view of Shchepinov, Rosell, Schacky and Everson.
In regards to claim 4, Shchepinov in view Rosell, Schacky and Everson disclose the method of claim 1, but does not further specifically disclose wherein the length of time between start of therapy and testing is from about 3 to about 45 days. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the length of time between start of therapy and testing is from about 3 to about 45 days, through routine experimentation.
Regarding claim 5, Shchepinov in view Rosell, Schacky and Everson disclose the method of claim 1, but does not further specifically disclose wherein the length of time between start of therapy and testing is at least about 14 days. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the length of time between start of therapy and testing is at least about 14 days, through routine experimentation.
Regarding claim 6, Shchepinov in view Rosell, Schacky and Everson disclose the method of claim 1, but does not further specifically disclose wherein the length of time between start of therapy and testing is at least about 30 days. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the length of time between start of therapy and testing is at least about 30 days, through routine experimentation.
In regards to claim 7, as described above, Everson teaches oral dosing with 300 mg caffeine and Shchepinov teaches D-DHA is delivered to retinal tissue via the blood stream and reaches effective doses above 1% after three days of dosing. However, one of ordinary skilled in the art from the description in mind of the references, can easily understand that an effective dose of D-DHA depends on the uptake of D-DHA in blood in a particular individual and the type, nature and stage of a particular retinal disease and could be established by routine experimentation and which is within the purview of one of ordinary skilled in the art.
In regards to claim 10, Shchepinov in view Rosell, Schacky and Everson, as described above, discloses the method of claim 1, but does not further specifically disclose wherein the concentration of deuterated docosahexaenoic acid is less than that provided by the standardized curve, then the clinician has the option of either modifying the patient's diet to reduce the amount of DHA-containing fat consumed per day and/or to increase the amount of drug administered. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the concentration of deuterated docosahexaenoic acid is less than that provided by the standardized curve, then the clinician has the option of either modifying the patient's diet to reduce the amount of DHA-containing fat consumed per day and/or to increase the amount of drug administered, through routine experimentation.
Claims 1-2, 4-7 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Shchepinov (U.S. Pat. 10058522) in view of Schacky (Nutrients 2021) and Everson et al (US 8,613,904 B2).
In regards to claim 1, Shchepinov teaches treating wet and/or dry age-related macular degeneration with an effective amount of a deuterated polyunsaturated fatty acid or its ester that is deuterated at one or more bis-allylic positions and claims docosahexaenoic acid as the deuterated fatty acid (abstract, claim 1 and 16). The deuterated polyunsaturated fatty acid or its ester (PUFA) is administered to the patient is about 5%-about 75% of the total amount of polyunsaturated fatty acid or fatty acid ester administered, and over the treatment period a significant amount of deuterated PUFA is incorporated into the patient's eye such that the amount of deuterated PUFA incorporated in the eye is sufficient to reduce or prevent autoxidation and cancel toxicity of undeuterated PUFA in the patient's eye (abstract, claims 1 and 16, Example 21). Shchepinov teaches that high PUFA content leads to increased PUFA peroxidation in the eye tissue and that PUFA oxidation by ROS is a factor in wet/dry AMD and the ROS damage within PUFA can be overcome by using PUFA less prone to oxidization such as deuterated forms (Col. 7 line 53-67, Col. 8 line 21-34). Shchepinov demonstrated blood testing of the subject to evaluate the blood serum concentration dosed subjects (example 17); and that in the case of essential and non-essential PUFAs, the supplemented stabilized materials can compete with other dietary uptake and biomanufacture to reduce the available disease causing species concentration (col. 15 line 50-54, see full document specifically areas cited).
While Shchepinov is not explicit on blood testing of the deuterated form, Shchepinov does expressly teach measuring and monitoring various blood components to ensure no anomalies or toxicity in the blood markers is known and that the patient is to be given an adequate/effective amount to reduce/cancel the toxicity of undeuterated PUFA wherein it is implicit that one would ascertain that the patient is being given an adequate/effective amount to reduce/cancel the toxicity of undeuterated PUFA such as blood testing for anomalies or toxicity.
Schacky teaches importance of determining blood level of DHA as the dietary intake of EPA and DHA (oral administration) does not correlate with the bioavailability for brain because of variability of adsorption during digestion. Schacky teaches that blood levels of EPA and DHA to clinical events or parameters usually found stronger correlations than those assessing dietary intake (pages 2-3).
Everson discloses a method for monitoring a patient for uptake of a compound (Cholate) utilizing isotopic analog of the compound for distinguishing from naturally present compound, wherein said method comprises: administering to said patient an effective dose of a isotopic compound (col 3 In 25-27); obtaining one or more blood samples from said patient after the start of oral administration (Abstract and claims 1-28). Everson teaches in one example, blood samples for measurement of cholate isotopes can be obtained at a baseline and several times after the baseline, for example, sample may be taken at 5, 10, 15, 20, 30, 45, 60, 75,90, 105, 120, 150, and less than 180 minutes post-dose where a total of 14 blood samples may be collected over 180 minutes (col. 7, lines 34-50; col. 11, lines 50-62). Everson teaches utilizing deuterated isotope of caffeine (D3 and D9) as test compound for quantitative assessment in serum over a concentration ranges after oral dosing with 300 mg caffeine (Col. 31). assessing the amount of a deuterated compound in said sample relative to the total amount of a non-deuterated compound (col 30 In 52 to col. 31, line 20 and claims 21-28). Everson teaches utilizing standard curve (col. 15; col. 26, lines 63-64).
Therefore, from the description in mind of the references, it would be obvious to one of ordinary skill in the art to test that the patient to verify by known means like a blood test seen in Shchepinov and Schacky -as to the amount of desirable D-PUFA (i.e. deuterated DHA) and amount of undesirable H-PUFA (i.e. DHA) present in the body (proportion/ratio) and adjust the dosage if needed to attain the therapeutic amount and produce the claimed invention; as Shchepinov expressly teaches that the undeuterated form is undesirable (i.e. DHA) and that an effective amount of the deuterated form is desirable (i.e. deuterated DHA) therein the patient is to be given an adequate/effective amount to reduce/cancel the toxicity of undeuterated PUFA; wherein it is prima facie obvious to test the patient by known means to evaluate/verify that the patient has an effective/desirable amount of the deuterated form circulating/available for the patient relative to the undeuterated form (proportion/ratio) to reduce/cancel the toxicity of undeuterated PUFA and adjust the dosage given to attain the therapeutically effective amount if inadequate. Shchepinov also teaches that the supplemented stabilized materials can compete with other dietary uptake and biomanufacture to reduce the available disease causing species concentration wherein it is also prima facie obvious to test the patient with known means as seen in Shchepinov to evaluate if an effective/desirable amount of D-PUFA is circulating/available for the patient relative to the level of the undesirable H-PUFA to (amount/ratio) to assure that the amount of the stable D-PUFA administered is effective to reduce/cancel the toxicity of undeuterated PUFA based on the dietary uptake, and to adjust the amount accordingly to attain the desired effective amount to reduce/cancel the toxicity of undeuterated PUFA if inadequate. Given the fact that Schacky teaches importance of determining blood level of DHA, which provides stronger correlation than those assessing dietary intake, it would be obvious to one of ordinary skilled in the art to envisage monitoring the deuterated DHA in blood of the orally administered D-DHA to access bioavailability of the D-DHA for retina with a reasonable expectation of success because Shchepinov teaches D-DHA is delivered to retinal tissue via the blood stream. From the description in mind of Everson, one of ordinary skilled in the art would readily understand that monitory blood level of deuterated DHA would involve periodically administering an effective dose of D-DHA, obtaining blood sample, accessing the amount of D-DHA in the sample relative to the total amount of DHA and incorporating comparing against a standard concentration curve based on specific dose of D-DHA in the assessment because the process of monitoring deuterated compound in blood has been disclosed by Everson. Moreover, it would be obvious to test regularly at a desired interval determined by the clinician to maintain the effective amount of the deuterated form compared to the undeuterated form to reduce/cancel the toxicity of undeuterated form.
In regards to claim 2, Everson discloses wherein the blood component being assessed is plasma (col 6 In 2-4 - ' ... plasma clearance of oral and intravenous cholic acid in subjects with and without chronic liver disease were studied ... '; col 11 In 54-57 - ' ... In one example, blood samples for measurement of chelate isotopes can be obtained at baseline and 5, 10, 15, 20, 30, 45, 60, 75,90, 105, 120, 150, and less than 180 minutes post-dose .. .') and assessing the amount of D-DHA in plasma would be obvious in view of Shchepinov, Rosell, Schacky and Everson.
In regards to claim 4, Shchepinov in view of Schacky and Everson disclose the method of claim 1, but does not further specifically disclose wherein the length of time between start of therapy and testing is from about 3 to about 45 days. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the length of time between start of therapy and testing is from about 3 to about 45 days, through routine experimentation.
Regarding claim 5, Shchepinov in view of Schacky and Everson disclose the method of claim 1, but does not further specifically disclose wherein the length of time between start of therapy and testing is at least about 14 days. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the length of time between start of therapy and testing is at least about 14 days, through routine experimentation.
Regarding claim 6, Shchepinov in view of Schacky and Everson disclose the method of claim 1, but does not further specifically disclose wherein the length of time between start of therapy and testing is at least about 30 days. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the length of time between start of therapy and testing is at least about 30 days, through routine experimentation.
In regards to claim 7, as described above, Everson teaches oral dosing with 300 mg caffeine and Shchepinov teaches D-DHA is delivered to retinal tissue via the blood stream and reaches effective doses above 1% after three days of dosing. However, one of ordinary skilled in the art from the description in mind of the references, can easily understand that an effective dose of D-DHA depends on the uptake of D-DHA in blood in a particular individual and the type, nature and stage of a particular retinal disease and could be established by routine experimentation and which is within the purview of one of ordinary skilled in the art.
In regards to claim 10, Shchepinov in view of Schacky and Everson, as described above, discloses the method of claim 1, but does not further specifically disclose wherein the concentration of deuterated docosahexaenoic acid is less than that provided by the standardized curve, then the clinician has the option of either modifying the patient's diet to reduce the amount of DHA-containing fat consumed per day and/or to increase the amount of drug administered. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the concentration of deuterated docosahexaenoic acid is less than that provided by the standardized curve, then the clinician has the option of either modifying the patient's diet to reduce the amount of DHA-containing fat consumed per day and/or to increase the amount of drug administered, through routine experimentation. The reference of Rosell is cited to show that oral administration of deuterated DHA analog useful for treating macular degeneration which shows normal incorporation and assimilation and for the teaching that high prevalence of DHA in retinal tissue indicates that DHA is effectively transferred from blood to retina (page 3, 2nd para).
Double Patenting
Claims 1-2, 4-7 and 10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 16 of U.S. Patent No. 10058522 in view of Schacky (Nutrients 2021) and Everson et al (US 8,613,904 B2).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claim is directed to treating wet and/or dry age-related macular degeneration with an effective amount of a deuterated polyunsaturated fatty acid or its ester that is deuterated at one or more bis-allylic positions wherein the deuterated fatty acid is docosahexaenoic acid, and is administered to the patient is about 5%-about 75% of the total amount of polyunsaturated fatty acid or fatty acid ester administered, and over the treatment period a significant amount of deuterated PUFA is incorporated into the patient's eye such that the amount of deuterated PUFA incorporated in the eye is sufficient to reduce or prevent autoxidation and cancel toxicity of undeuterated PUFA in the patient's eye (claim 16, dependent from claim 1).
While the patented claim is not explicit on blood testing of the deuterated form, the patented claim recites that the patient is to be given an adequate/effective amount to reduce/cancel the toxicity of undeuterated PUFA/DHA wherein it is implicit that one would ascertain that the patient is to be given an adequate/effective amount to reduce/cancel the toxicity of undeuterated DHA such as blood testing for anomalies or toxicity.
Schacky teaches importance of determining blood level of DHA as the dietary intake of EPA and DHA (oral administration) does not correlate with the bioavailability for brain because of variability of adsorption during digestion. Schacky teaches that blood levels of EPA and DHA to clinical events or parameters usually found stronger correlations than those assessing dietary intake (pages 2-3).
Everson discloses a method for monitoring a patient for uptake of a compound (Cholate) utilizing isotopic analog of the compound for distinguishing from naturally present compound, wherein said method comprises: administering to said patient an effective dose of a isotopic compound (col 3 In 25-27); obtaining one or more blood samples from said patient after the start of oral administration (Abstract and claims 1-28). Everson teaches in one example, blood samples for measurement of cholate isotopes can be obtained at a baseline and several times after the baseline, for example, sample may be taken at 5, 10, 15, 20, 30, 45, 60, 75,90, 105, 120, 150, and less than 180 minutes post-dose where a total of 14 blood samples may be collected over 180 minutes (col. 7, lines 34-50; col. 11, lines 50-62). Everson teaches utilizing deuterated isotope of caffeine (D3 and D9) as test compound for quantitative assessment in serum over a concentration ranges after oral dosing with 300 mg caffeine (Col. 31). assessing the amount of a deuterated compound in said sample relative to the total amount of a non-deuterated compound (col 30 In 52 to col. 31, line 20 and claims 21-28). Everson teaches utilizing standard curve (col. 15; col. 26, lines 63-64).
Therefore, from the description in mind of the references, it would be obvious to one of ordinary skill in the art to test that the patient to verify by known means like a blood test suggested by Schacky for measuring to the amount of desirable D-PUFA (i.e. deuterated DHA) and amount of undesirable H-PUFA (i.e. DHA) present in the body (proportion/ratio) and adjust the dosage if needed to attain the therapeutic amount and produce the claimed invention; as the patented claim expressly claims that the un-deuterated form is toxic/undesirable and that an effective amount of the deuterated form is desirable wherein the patient is to be given an adequate/effective amount to reduce/cancel the toxicity of un-deuterated DHA, it is prima facie obvious to test the patient by known means to evaluate/verify that the patient has an effective/desirable amount of the deuterated form is circulating/available for the patient relative to the un-deuterated form (proportion/ratio) to reduce/cancel the toxicity of un-deuterated DHA and adjust the amount given to attain the therapeutically effective amount if inadequate. It would be prima facie obvious to test regularly at a desired interval determined by the clinician to maintain the effective amount of the deuterated form compared to the un-deuterated form to reduce/cancel the toxicity of un-deuterated form. Given the fact that Schacky teaches importance of determining blood level of DHA, which provides stronger correlation than those assessing dietary intake, it would be obvious to one of ordinary skilled in the art to envisage monitoring the deuterated DHA in blood of the orally administered D-DHA to access bioavailability of the D-DHA for retina with a reasonable expectation of success because Shchepinov teaches D-DHA is delivered to retinal tissue via the blood stream. From the description in mind of Everson, one of ordinary skilled in the art would readily understand that monitory blood level of deuterated DHA would involve periodically administering an effective dose of D-DHA, obtaining blood sample, accessing the amount of D-DHA in the sample relative to the total amount of DHA and incorporating comparing against a standard concentration curve based on specific dose of D-DHA in the assessment because the process of monitoring deuterated compound in blood has been disclosed by Everson. Moreover, it would be obvious to test regularly at a desired interval determined by the clinician to maintain the effective amount of the deuterated form compared to the un-deuterated form to reduce/cancel the toxicity of un-deuterated form.
In regards to claim 2, Everson discloses wherein the blood component being assessed is plasma (col 6 In 2-4 - ' ... plasma clearance of oral and intravenous cholic acid in subjects with and without chronic liver disease were studied ... '; col 11 In 54-57 - ' ... In one example, blood samples for measurement of chelate isotopes can be obtained at baseline and 5, 10, 15, 20, 30, 45, 60, 75,90, 105, 120, 150, and less than 180 minutes post-dose .. .') and assessing the amount of D-DHA in plasma would be obvious in view of Shchepinov, Rosell, Schacky and Everson.
In regards to claim 4, the patent claims in view of the references, disclose the method of claim 1, but does not further specifically disclose wherein the length of time between start of therapy and testing is from about 3 to about 45 days. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the length of time between start of therapy and testing is from about 3 to about 45 days, through routine experimentation.
Regarding claim 5, US patent ‘522 in view of Schacky and Everson disclose the method of claim 1, but does not further specifically disclose wherein the length of time between start of therapy and testing is at least about 14 days. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the length of time between start of therapy and testing is at least about 14 days, through routine experimentation.
Regarding claim 6, US patent ‘522 in view of Schacky and Everson disclose the method of claim 1, but does not further specifically disclose wherein the length of time between start of therapy and testing is at least about 30 days. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the length of time between start of therapy and testing is at least about 30 days, through routine experimentation.
In regards to claim 7, as described above, Everson teaches oral dosing with 300 mg caffeine and Shchepinov teaches D-DHA is delivered to retinal tissue via the blood stream and reaches effective doses above 1% after three days of dosing. However, one of ordinary skilled in the art from the description in mind of the references, can easily understand that an effective dose of D-DHA depends on the uptake of D-DHA in blood in a particular individual and the type, nature and stage of a particular retinal disease and could be established by routine experimentation and which is within the purview of one of ordinary skilled in the art.
In regards to claim 10, US patent “522 in view of Schacky and Everson, as described above, discloses the method of claim 1, but does not further specifically disclose wherein the concentration of deuterated docosahexaenoic acid is less than that provided by the standardized curve, then the clinician has the option of either modifying the patient's diet to reduce the amount of DHA-containing fat consumed per day and/or to increase the amount of drug administered. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the concentration of deuterated docosahexaenoic acid is less than that provided by the standardized curve, then the clinician has the option of either modifying the patient's diet to reduce the amount of DHA-containing fat consumed per day and/or to increase the amount of drug administered, through routine experimentation.
Claims 1-2, 4-7 and 10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8-9, 16-21 of U.S. Patent No. 11285125 in view of Wade et al. (The synthesis of the very long chain polyunsaturated fatty acid (VLC-PUFA) 32:6 n-3).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims are directed to treating an eye condition including age-related macular degeneration (embracing both wet and dry forms) with an effective amount of a deuterated polyunsaturated fatty acid or its ester that is deuterated at one or more bis-allylic positions wherein the deuterated fatty acid includes docosahexaenoic acid, and is administered to the patient is about 1%-about 99% of the total amount of polyunsaturated fatty acid or fatty acid ester administered orally (claim 20), and over the treatment period a significant amount of deuterated PUFA is incorporated into the patient's eye such that the amount of deuterated PUFA incorporated in the eye is sufficient to reduce or prevent autoxidation and cancel toxicity of undeuterated PUFA in the patient's eye.
While the patented claims are not explicit on blood testing of the deuterated form, the patented claim recites that the patient is to be given an adequate/effective amount to reduce/cancel the toxicity of undeuterated PUFA/DHA wherein it is implicit that one would ascertain that the patient is to be given an adequate/effective amount to reduce/cancel the toxicity of un-deuterated DHA such as blood testing for anomalies or toxicity.
Schacky teaches importance of determining blood level of DHA as the dietary intake of EPA and DHA (oral administration) does not correlate with the bioavailability for brain because of variability of adsorption during digestion. Schacky teaches that blood levels of EPA and DHA to clinical events or parameters usually found stronger correlations than those assessing dietary intake (pages 2-3).
Everson discloses a method for monitoring a patient for uptake of a compound (Cholate) utilizing isotopic analog of the compound for distinguishing from naturally present compound, wherein said method comprises: administering to said patient an effective dose of a isotopic compound (col 3 In 25-27); obtaining one or more blood samples from said patient after the start of oral administration (Abstract and claims 1-28). Everson teaches in one example, blood samples for measurement of cholate isotopes can be obtained at a baseline and several times after the baseline, for example, sample may be taken at 5, 10, 15, 20, 30, 45, 60, 75,90, 105, 120, 150, and less than 180 minutes post-dose where a total of 14 blood samples may be collected over 180 minutes (col. 7, lines 34-50; col. 11, lines 50-62). Everson teaches utilizing deuterated isotope of caffeine (D3 and D9) as test compound for quantitative assessment in serum over a concentration ranges after oral dosing with 300 mg caffeine (Col. 31). assessing the amount of a deuterated compound in said sample relative to the total amount of a non-deuterated compound (col 30 In 52 to col. 31, line 20 and claims 21-28). Everson teaches utilizing standard curve (col. 15; col. 26, lines 63-64).
Therefore, from the description in mind of the references, it would be obvious to one of ordinary skill in the art to test that the patient to verify by known means like a blood test suggested by Schacky for measuring to the amount of desirable D-PUFA (i.e. deuterated DHA) and amount of undesirable H-PUFA (i.e. DHA) present in the body (proportion/ratio) and adjust the dosage if needed to attain the therapeutic amount and produce the claimed invention; as the patented claim expressly claims that the un-deuterated form is toxic/undesirable and that an effective amount of the deuterated form is desirable wherein the patient is to be given an adequate/effective amount to reduce/cancel the toxicity of un-deuterated DHA, it is prima facie obvious to test the patient by known means to evaluate/verify that the patient has an effective/desirable amount of the deuterated form is circulating/available for the patient relative to the un-deuterated form (proportion/ratio) to reduce/cancel the toxicity of un-deuterated DHA and adjust the amount given to attain the therapeutically effective amount if inadequate. It would be prima facie obvious to test regularly at a desired interval determined by the clinician to maintain the effective amount of the deuterated form compared to the un-deuterated form to reduce/cancel the toxicity of un-deuterated form. Given the fact that Schacky teaches importance of determining blood level of DHA, which provides stronger correlation than those assessing dietary intake, it would be obvious to one of ordinary skilled in the art to envisage monitoring the deuterated DHA in blood of the orally administered D-DHA to access bioavailability of the D-DHA for retina with a reasonable expectation of success because Shchepinov teaches D-DHA is delivered to retinal tissue via the blood stream. From the description in mind of Everson, one of ordinary skilled in the art would readily understand that monitory blood level of deuterated DHA would involve periodically administering an effective dose of D-DHA, obtaining blood sample, accessing the amount of D-DHA in the sample relative to the total amount of DHA and incorporating comparing against a standard concentration curve based on specific dose of D-DHA in the assessment because the process of monitoring deuterated compound in blood has been disclosed by Everson. Moreover, it would be obvious to test regularly at a desired interval determined by the clinician to maintain the effective amount of the deuterated form compared to the un-deuterated form to reduce/cancel the toxicity of un-deuterated form.
In regards to claim 2, Everson discloses wherein the blood component being assessed is plasma (col 6 In 2-4 - ' ... plasma clearance of oral and intravenous cholic acid in subjects with and without chronic liver disease were studied ... '; col 11 In 54-57 - ' ... In one example, blood samples for measurement of chelate isotopes can be obtained at baseline and 5, 10, 15, 20, 30, 45, 60, 75,90, 105, 120, 150, and less than 180 minutes post-dose .. .') and assessing the amount of D-DHA in plasma would be obvious in view of Shchepinov, Rosell, Schacky and Everson.
In regards to claim 4, the patent claims in view of the references, disclose the method of claim 1, but does not further specifically disclose wherein the length of time between start of therapy and testing is from about 3 to about 45 days. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the length of time between start of therapy and testing is from about 3 to about 45 days, through routine experimentation.
Regarding claim 5, US patent ‘125 in view of Schacky and Everson disclose the method of claim 1, but does not further specifically disclose wherein the length of time between start of therapy and testing is at least about 14 days. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the length of time between start of therapy and testing is at least about 14 days, through routine experimentation.
Regarding claim 6, US patent ‘125 in view of Schacky and Everson disclose the method of claim 1, but does not further specifically disclose wherein the length of time between start of therapy and testing is at least about 30 days. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the length of time between start of therapy and testing is at least about 30 days, through routine experimentation.
In regards to claim 7, as described above, Everson teaches oral dosing with 300 mg caffeine and Shchepinov teaches D-DHA is delivered to retinal tissue via the blood stream and reaches effective doses above 1% after three days of dosing. However, one of ordinary skilled in the art from the description in mind of the references, can easily understand that an effective dose of D-DHA depends on the uptake of D-DHA in blood in a particular individual and the type, nature and stage of a particular retinal disease and could be established by routine experimentation and which is within the purview of one of ordinary skilled in the art.
In regards to claim 10, US patent “125 in view of Schacky and Everson, as described above, discloses the method of claim 1, but does not further specifically disclose wherein the concentration of deuterated docosahexaenoic acid is less than that provided by the standardized curve, then the clinician has the option of either modifying the patient's diet to reduce the amount of DHA-containing fat consumed per day and/or to increase the amount of drug administered. However, it would have been obvious to one of ordinary skill in the art to create the method wherein the concentration of deuterated docosahexaenoic acid is less than that provided by the standardized curve, then the clinician has the option of either modifying the patient's diet to reduce the amount of DHA-containing fat consumed per day and/or to increase the amount of drug administered, through routine experimentation. Everson is cited to show that monitoring of blood level of orally administered deuterated compound provides
Response to argument
Applicant's arguments filed 08/26/2026 have been fully considered but they are not persuasive to overcome the rejections under 35 USC 103 and non-statutory double patenting.
Regarding rejection under 35 USC 103, Applicant argued that the reference of Schepinov ‘596 does not teach obtaining a blood sample from a patient and hence is incapable of monitoring the patient for uptake of deuterated decosahexaenoic acid. Applicant argued that the reference of Rosell teaches incorporation of D-DHA in retinal epithelia cells but fails to describe or suggest measurement of deuterated docosahexaenoic acid in the blood of a patient. Applicant argued that that the reference of Schacky teaches that blood levels of naturally occurring EPA and DHA correlate with clinical parameters better than assessment of dietary intake but the reference fails to teach deuterated compounds and measuring a deuterated species relative to the undeuterated counterpart. Applicant argued that Everson fails to teach of suggest a standard concentration curve constructed as a function of specific therapeutic dose employed. Applicant further argued that the combination of Shchepinov '596, Rosell, Schacky and Everson fails to teach or suggest each and every limitation of the invention recited in claim 1.
The above arguments have fully been considered but are not found persuasive because the ‘‘mere existence of differences between the prior art and an invention does not establish the invention’s nonobviousness.’’ The gap between the prior art and the claimed invention may not be ‘‘so great as to render the [claim] nonobvious to one reasonably skilled in the art.’’ In determining obviousness, neither the particular motivation to make the claimed invention nor the problem the inventor is solving controls. The proper analysis is whether the claimed invention would have been obvious to one of ordinary skill in the art after consideration of all the facts. Applicants must realize that one cannot show nonobviousness by attacking references individually wherein the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merk & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Obviousness can only be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fines, 837 F.2d 1071, 5USPQ2d 1596 (Fed. Cir. 1988) and In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir.1992). The test for combining references is what the combination of disclosures, taken as a whole, would suggest to one of ordinary skill in the art. See: In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); or, In re McLaughlin, 170 USPQ 209 (CCPA 1971). References are evaluated by what they suggest to one versed in the art, rather than by their specific disclosures. See: In re Bozek, 163 USPQ 545 (CCPA 1969). A person of ordinary skill in the art, using common knowledge and common sense, is capable of fitting the teachings of multiple references together like pieces of a puzzle, regardless of the specific problem being addressed by the individual references. Any need or problem known at the time of the invention can provide a reason for combining elements of the different references. A person of ordinary skill in the art is also a person of ordinary creativity. In this case, Shchepinov teaches administering deuterated DHA (D-DHA) orally as ethyl ester at different time periods for treatment of retina. Shchepinov teaches that D-DHA is delivered to retinal tissue via the blood stream and reaches effective doses above 1% after three days of dosing (para [0183]). Shchepinov teach periodically administering deuterated PUFA including D-DHA but does not teach detection/accessing the amount of D-DHA in blood sample for monitoring uptake in blood. The reference of Schacky is cited because the reference teaches importance of determining blood level of DHA because the reference teaches that blood levels of EPA and DHA to clinical events or parameters usually found stronger correlations than those assessing dietary intake (pages 2-3). Therefore, from the description in mind of the references, one of ordinary skilled in the art would readily understand that deuterated PFU is delivered to retinal tissue via the blood stream and its important to monitor the blood level of deuterated PFU as a measure of bioavailability to tissue rather than in the orally administered sample because blood levels of PFU (EPA and DHA) to clinical events or parameters usually found stronger correlations than those assessing dietary intake. Both Shchepinov teaches deuterated PUFA for treatment of neurological or retinal diseases by reducing lipid autooxidation (Shchepinov). Given the teaching that both Shchepinov and Rosell teach deuterated-DHA for treatment of macular degeneration and administration of deuterated DHA (D-DHA) orally, and given the fact that Schacky teaches importance of determining blood level of DHA, which provides stronger correlation than those assessing dietary intake, it would be obvious to one of ordinary skilled in the art to envisage monitoring the deuterated DHA in blood of the orally administered D-DHA to access bioavailability of the D-DHA for retina with a reasonable expectation of success because Rosell teaches DHA is effectively transferred from blood to retina and Shchepinov teaches D-DHA is delivered to retinal tissue via the blood stream. From the description in mind of Everson, one of ordinary skilled in the art would readily understand that monitory blood level of deuterated DHA would involve periodically administering an effective dose of D-DHA, obtaining blood sample, accessing the amount of D-DHA in the sample relative to the total amount of DHA and incorporating comparing against a standard concentration curve based on specific dose of D-DHA in the assessment because the process of monitoring deuterated compound in blood has been disclosed by Everson.
The double patenting rejections are maintained because Applicant’s arguments are based on the same rationale and the same arguments as described above, also applicable for the double patenting rejections.
Conclusion
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.
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/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678
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