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 .
Claim Status
Claims 1-2,4-9,13, and 23 are pending.
Claim Rejections - 35 USC § 112
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 5-9 and 13 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.
Regarding claims 5-9, the phrase “during a/the stage of heart preservation…” renders the claim indefinite because it is unclear what the phrase, specifically the term, “a stage” (claim 5) or “the stage” (claims 6-9) encompasses in the context of the claims. It is unclear where in the method of the independent claim 1, the limitations set forth by claims 5-9 (i.e. oxygenated perfusate is fed…,potassium ions concentration in perfusate is maintained…,…if the heart begins…, the heart does not beat…, blood clotting ability is monitored,..) are to be included.
For examination purposes with respect to prior art, any method of preserving a donor that includes the limitations set forth by claims 5-9, in any manner and meeting the recited active methods steps will be considered within the metes and bounds of claims 5-9.
Regarding claim 13, the phrase, “wherein the volumetric perfusion divided by the mass of the heart rate is maintained in the range of 0.3-1.2 mL/min/g…” renders the claim indefinite because it is unclear what the phrase , specifically the portion, “ divided by the mass of the heart rate” encompasses in the context of the claim. It is unclear what the components of the ratio are and how the unit of measure for the range is achieved, because the volume of perfusate divided by heart mass would have units of mL/g. There are key terms missing to fully understand the scope of the limitation of claim 13.
For examination purposes with respect to prior art, any method of preserving a donor heart with the data to formulate the ratio of perfusate flow rate to heart mass (mL/min/g) will be considered within the metes and bounds of claim 13, due to the compatible units of measurement.
Appropriate correction or clarification is required.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 5-6, and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kothari (Journal of cardiovascular development and disease, 2023), evidenced by Mohite et al (CTSNET.org, 2020) and Edelman et al (Annals of cardiothoracic surgery, 2013).
Kothari teaches that heart transplantation is the gold standard treatment for end stage heart failure and there are two systems for prolonged organ preservation, Transmedic Organ Care System (OCS) and XVIVO device. The OCS system allows for ex vivo normothermic perfusion and the XVIVO device allows for hypothermic perfusion. (See, Abstract).
Kothari teaches that for ex-vivo normothermic perfusion with the OCS there are two methods that can be done for harvesting the heart depending on the patient outcome prior to donation (See, p2 paragraph 5). For brain death (DBD) donors once the organ has been checked for allograft quality, a cardioplegia cannula is placed into the aorta and a venous cannula is placed in the right artium. Donor blood is collected, heparinized, to then be added to the OCS system to prime the system and to be mixed with the perfusion solution. The allograft is then procured with incisions at various major vessel sites. (See, p2 paragraph 5).
Kothari teaches that once the heart is removed from donor, it is prepared for attachment to the OCS for perfusion, which includes cannulating the aorta and pulmonary arteries that are attached to the circuit and the coronary perfusion with oxygenated blood begins (See, p 2-3, Figure 1). The perfusion solution is a mixture of donor blood, electrolytes, dextrose, heparin, steroids, insulin, and antibiotics to maintain the organ. Kothari teaches that generally after a few minutes of perfusion, the heart begins contracting and that the OCS has a built in defibrillation pads that allow for conversion to sinus rhythm (See, p10). The OCS creates a closed circuit and the ideal flow rate is approximately, 700-800 mL/min (See, p3 and Figure 2A).
Regarding claim 1 and 8, Kothari teaches a method of preserving a donor heart, comprising perfusing donor heart with oxygenated blood based perfusate, wherein the donor heart is predominantly kept in a non-beating state. The donor heart isn’t beating until the continuous perfusion and that generally happens, implying it doesn’t always and needs assistance, therefore reading on predominantly non-beating state, especially during the transfer from the donor to the OCS.
Regarding claim 2, following the discussion above, Kothari teaches that during procurement a cannula is placed into the aorta for the cardioplegia solution. Therefore, the donor heart is put in a non-beating state with the cardioplegia solution and the cardioplegic solution is administered before the preservation in the OCS is initiated.
Mohite et al provides a user guide for the Transmedic OCS that details the use of Brettschneider (HTK) also known as Custodiol, a cardioplegic solution, during procurement transfer to OCS and thus the procured donor heart is in a non-beating state (See, p3). Edelman et al details the components and concentrations of Custodiol; Custodiol has a K+ (potassium ion) concentration of 9 mmol/L (=0.35188g/L) (See, p718 Table 1).
Regarding claim 5, following the discussion above, Kothari teaches cannulating the aorta and pulmonary arteries that are attached to the circuit and the coronary perfusion with oxygenated blood begins (See, p 2-3, Figure 1). The figure legend provides a guide for the blood /perfusion mix goes through, blood enters the heart through the aortic cannula and travels retrogradely to the coronary arteries. Deoxygenated blood enters the coronary sinus and drains to the right artium and right ventricle, where it is ejected out of pulmonary artery and then drained to the reservoir. The left atrial vent also drains to the reservoir. A pump then pushes the blood/perfusate mixture through the gas exchanger and heater, to recirculate through the donor heart (See, Figure 1 p3).
Regarding claim 6, following the discussion above, Kothari teaches the OCS is closed circuit and that the perfusion solution should include electrolytes. The Custodiol used for cardioplegia has potassium ions concentration of 9 mmol/L.
Edelman et al teaches in Table 1, the ingredients and concentrations of Custodiol (See, p718 Table 1). Edelman et al teaches that custodiol has a K+ (potassium ion) concentration of 9 mmol/L (=0.35188g/L), Mg2+ (magnesium ions) concentration of 4 mmol/L (= 0.097 grams/L), and a pH of 7.02-1.20.
Therefore claims 1,2,5,6, and 8 are rejected as being anticipated by Kothari and evidenced by Mohite et al and Edelman et al.
Claims 1 and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yang et al (The Annals of thoracic surgery, 2013).
Yang et al teaches that preservation of donor hearts in beating status with continuous, normothermic, blood perfusion is an effective approach for long-term preservation and for heart transplantation (See, Abstract).
Regarding claim 1, Yang et al teaches in their method that for group A of pigs the hearts were procured, then placed in a perfusion solution of autologous blood depleted of leukocytes (by filtration) in a perfusion system. After the cannulas for the continuous perfusion are properly placed in major vessels, the heart is removed from the cavity and preserved in the storage reservoir for 8 hours in a beating state in normothermic blood perfusion. The perfusion rate is 100-120 mL/min, pressure was within 45 to 55 mm Hg, and temperature 37°C. (See, p2029 Methods). This reads on the limitations of the method of claim 1, wherein perfusing the donor heart with oxygenated blood based perfusate, wherein the donor heart is predominantly kept in a non-beating state, as the blood is mixed with the perfusate and the perfusion system provides gas during the circulation circuit for oxygenation, and lastly because the heart is stopped during procurement, it is predominately not beating.
Regarding claim 9, following the discussion above, Yang et al teaches that after procurement the perfusion solution had 3 mg of heparin, and throughout the process the activated clotting time (ACT) was tested and it was longer than 480 seconds, therefore no more heparin was administered. This reads on the limitation of claim 9 where blood clotting ability is monitored and if less than 400 seconds, ACT is adjusted with heparin, due to the initial dose of heparin to get it within the necessary range.
Therefore claims 1 and 9 are rejected as being anticipated by Yang et al.
Claim Rejections - 35 USC § 103
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.
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.
Claim 4 is rejected under pre-AIA 35 U.S.C. 103 as being unpatentable over Kothari (Journal of cardiovascular development and disease, 2023) as applied to claim 1,2,5-6,8 above, and further in view of Mohite et al (CTSNet.org, doi:10.25373/ctsnet.13374056, 2020).
The teachings of Kothari are set forth above.
Regarding claim 4, following the discussion above, Kothari teaches a method for ex-vivo normothermic preservation with the Transmedic OCS.
Kothari does not teach the temperature or a range at which the method of normothermic preservation is completed in.
Mohite et al provides a user guide for the Transmedic OCS that details a method to use the system for normothermic preservation of donor heart. The Transmedic organ Care System (OCS) is a commercially available system that allows a beating donor heart to be maintained a normothermic conditions of 34°C and perfused with oxygenated perfusate/blood during the preservation process (See, p2). It would therefore have been at least prima facie obvious to have performed the ex-vivo normothermic preservation with the Transmedic OCS of Kothari at a temperature of 34°C based on the teachings of Mohite et al. The rationale for this conclusion of obviousness is the explicit teaching of Mohite et al. One would have had a reasonable expectation of successfully carrying out the method of Kothari at 34°C based on the disclosure of Mohrite et al. Therefore, claim 4 is rendered obvious over Kothari in view of Mohite et al.
Claims 7,13 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Kothari (Journal of cardiovascular development and disease, 2023), evidenced by Edelman et al (Annals of cardiothoracic surgery, 2013).
The teachings of Kothari are set forth above.
Regarding claim 7, following the discussion above, Kothari teaches that for ex-vivo normothermic perfusion with the OCS there are two methods that can be done for harvesting the heart depending on the patient outcome prior to donation (See, p2 paragraph 5). For brain death (DBD) donors once the organ has been checked for allograft quality, a cardioplegia cannula is placed into the aorta and a venous cannula is placed in the right artium.
Kothari does not explicitly teach the limitation, that if the heart begins to contract or enters bradycardia, to administer an additional dose of potassium ions into the perfusate.
However, it would have been prima facie obvious to a person of ordinary skill in the art to have modified the method of Kothari to comprise an additional step of adding more potassium ions or cardioplegic solution with the potassium ions to a donor heart that has not fully stopped beating. One would be motivated to make this modification because the method requires a non-beating heart for transfer from donor to OCS for preservation, therefore ensuring it is in a non-beating state is essential.
Further, one would have a reasonable expectation of success because potassium ions are part of cardioplegia administered initially to achieve a non-beating state and is included in the perfusate solution for further maintenance of the donor heart.
Therefore claim 7 is rendered obvious over Kothari.
Regarding claim 13, following the discussion above, Kothari teaches that heart transplantation is the gold standard treatment for end stage heart failure and there are two systems for prolonged organ preservation, an ex-vivo normothermic perfusion with the Transmedic Organ Care System (OCS) and an ex-vivo hypothermic perfusion with the XVIVO device. (See, Abstract).
The above claims focus on the teachings for the OCS, an ex-vivo normothermic method but for claim 13, the embodiment for the XVIVO system will be used as it reads on the limitations of the independent claim (claim 1) and those of claim 13 being addressed.
Kothari teaches the method for using the XVIVO system that continuously perfuses the heart with cold, oxygenated cardioplegic solution that includes nutrients, hormones, and red blood cells (See, p7 paragraph 4). Therefore, with the XVIVO system, the donor heart is perfused with oxygenated blood-based perfusate, and kept in a predominantly non-beating state due to the cardioplegia in the perfusate. The device is designed to maintain an average aortic pressure of 20 mm Hg and blood flow rate of 150-200 mL/min in a non-beating state (See, p7 paragraph 4). Aortic pressure is used as an indicator of coronary perfusion pressure. The average human heart can range in weight from 230-350 grams depending on size and gender, therefore the ratio of perfusion to mass of heart would range from, 0.05-0.08 mm Hg/g. The second ratio of blood flow to heart mass would have a range of (0.43-0.65 mL/min/g) to (0.57-0.87 mL/min/g).
Kothari provides a range for the ratios of claim 13 and it varies based on the size of the donor heart, it would be readily determinable by one having ordinary skill in the art by routine experimentation to find the optimal perfusion to mass ratio or blood flow to mass ratio. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation (See MPEP 2144.05).
Therefore, claim 13 is rendered obvious over Kothari.
Regarding claim 23, following the discussion above, Kothari teaches the method of OCS for heart preservation and the use of perfusion solution, that is a mixture of donor blood, electrolytes, dextrose, heparin, steroids, insulin, and antibiotics to maintain the organ (See, p3). Potassium ions and magnesium chloride are known electrolytes. The Kothari method also teaches the use of cardioplegia, such as Custodiol. Edelman et al teaches in Table 1, the ingredients and concentrations of Custodiol (See, p718 Table 1). Table 1 of Edelman et al shows custodiol has a K+ (potassium ion) concentration of 9 mmol/L (=0.35188g/L), Mg2+ (magnesium ions) concentration of 4 mmol/L (= 0.097 grams/L), and a pH of 7.02-1.20. Edelman et al also teaches that the components of custodiol have a high histidine content buffers the acidosis to maintain the pH (See, p718 col 1 para 1). This shows that the perfusate would have an initial concentration of these values that would then be combined with the solution taught in the method of Kothari.
Kothari provides necessary elements required by the perfusion solution of claim 23 and it varies based on the volume of perfusate used in the OCS or other preservation system, it would be readily determinable by one having ordinary skill in the art by routine experimentation to find the optimal grams of electrolytes and buffer system for the perfusion solution. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation (See MPEP 2144.05).
Therefore claim 23 is rendered obvious over Kothari and evidenced by Edelman et al.
Conclusion
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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