DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 09/26/2025, in which claims 34, 42, 51, and 54 are amended and claims 1-33 and 41 are canceled.
Claims 34-40 and 42-60 are pending and are examined on the merits herein.
Priority
The instant application is a continuation of 17/743,154 filed 05/12/2022, which claims domestic benefit to provisional application 63/187,624, filed on 05/12/2021.
Information Disclosure Statement
The information disclosure statements (IDS) dated 10/29/2025 and 12/05/2025 comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the information disclosure statements are being considered by the examiner.
Rejections Withdrawn
Applicant’s amendment and remarks, filed 09/26/2025, with respect that claims 34-35, 38-39, 41-42, 55-57 are rejected under 35 U.S.C. 103 as being unpatentable over Gleich in view of Xie and Schwartz has been fully considered and is persuasive, as claim 34 is amended to recite permeating at least some of the heparin solution through the fractionation membrane under an applied pressure and adding about 6-12 diafiltration volumes (DVs) of the solvent, claim 42 is amended to alter the range of the filtration volume from 10-20 DV to 7-8 DV, and claim 41 is canceled.
This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 09/26/2025, with respect that claims 36-37 and 49 are rejected under 35 U.S.C. 103 as being unpatentable over in view of Xie and Schwartz as applied to claims 34 and 46, further in view of Lormeau has been fully considered and is persuasive, as claim 34 is amended to recite permeating at least some of the heparin solution through the fractionation membrane under an applied pressure and adding about 6-12 diafiltration volumes (DVs) of the solvent.
This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 09/26/2025, with respect that claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Gleich in view of Xie and Schwartz, as applied to claims 34 and 39, further in view of Millipore and Hemavathi has been fully considered and is persuasive, as claim 34 is amended to recite permeating at least some of the heparin solution through the fractionation membrane under an applied pressure and adding about 6-12 diafiltration volumes (DVs) of the solvent.
This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 09/26/2025, with respect that claims 43-44 are rejected under 35 U.S.C. 103 as being unpatentable over Gleich in view of Xie and Schwartz, as applied to claim 34 above, further in view of Flengsrud has been fully considered and is persuasive, as claim 34 is amended to recite permeating at least some of the heparin solution through the fractionation membrane under an applied pressure and adding about 6-12 diafiltration volumes (DVs) of the solvent.
This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 09/26/2025, with respect that claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over Gleich in view of Xie and Schwartz, as applied to claim 34 above, further in view of Flengsrud has been fully considered and is persuasive, as claim 34 is amended to recite permeating at least some of the heparin solution through the fractionation membrane under an applied pressure and adding about 6-12 diafiltration volumes (DVs) of the solvent.
This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 09/26/2025, with respect that claims 34-39, 41-45, and 54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 11,712,447 B2 has been fully considered and is persuasive, as claims 34 and 54 are amended to recite permeating at least some of the heparin solution through the fractionation membrane under an applied pressure and adding about 6-12 diafiltration volumes (DVs) of the solvent.
This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 09/26/2025, with respect that claims 40, 55-56, and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 11,712,447 B2 further in view of Millipore (Millipore application Note, 2008; PTO-892) and Hemavathi been fully considered and is persuasive, as claim 34 is amended to recite permeating at least some of the heparin solution through the fractionation membrane under an applied pressure and adding about 6-12 diafiltration volumes (DVs) of the solvent.
This rejection has been withdrawn.
The following are maintained and new grounds of rejection necessitated by Applicant’s amendment, in which claims 34 and 54 are amended to recite permeating at least some of the heparin solution through the fractionation membrane under an applied pressure and adding about 6-12 diafiltration volumes (DVs) of the solvent. Additionally, claim 42 is amended to alter the range of the filtration volume from 10-20 DV to 7-8 DV, and claim 51 is amended to alter the range of the filtration volume from 10-20 DV to 6-12 DV.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 39 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 39 depends from independent claim 34 and recites wherein fractionating the heparin solution by tangential flow filtration comprises permeating at least some of the heparin solution
through the fractionation membrane under an applied pressure to yield a retentate comprising the fractionated heparin. However, claim 34 limits a method of manufacturing fractionated heparin in which fractionating the heparin solution by tangential flow filtration comprises permeating at least some of the heparin solution through the fractionation membrane under an applied pressure to yield a retentate comprising the fractionated heparin. This claim 39 fails to further limit claim 34. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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.
Claims 34-35, 38-40, 42, and 54-57 are rejected under 35 U.S.C. 103 as being unpatentable over Gleich et al. (WO 2021/163190; IDS 21/06/2023) in view of Xie et al. (Carbohyd. Polym., 2014; IDS 21/06/2023), Schwartz et al. (Pall Corp. bulletin, 2014; IDS 21/06/2023), and Millipore (Millipore application Note, 2008; PTO-892 03/28/2025).
Gleich teaches a method of treating a tissue comprising administering a fractionated heparin with an average molecular weight of about 20-40 kDa, where at least 50% of the heparin chains have a molecular weight of at least 20 kDa ([00153] and (claim 19). Gleich teaches that the methods of making high molecular weight heparin compositions can be carried out using any method known in the art for separating molecules of differing molecular weights, including fractionation by gel permeation chromatography [00177] of medicinal grade heparin, USP at an initial concentration of 0.9 grams in water to reach 2.4 mL of solution [00220]. Gleich further teaches that the heparin may be heparin sodium [00165].
The teachings of Gleich differ from that of the instantly claimed invention in that Gleich does not teach that the heparin is separated by tangential flow filtration, the MWCO of the membrane, or the addition of diafiltration volumes.
Xie teaches that gel filtration chromatography is not only complicated but also expensive and that ultrafiltration membrane process has many advantages including low cost, energy savings, and high efficiency, and is used in the purification of polysaccharides (paragraph bridging pages 479-480). Xie teaches that the ultrafiltration is accomplished using tangential flow filtration (page 480, paragraph 4). Xie teaches that polysaccharides are separated by into fractions of varying MW using filters with different MW cut off (MWCO) values, which allow isolation of a target molecular weight (figure 2, and page 480, paragraphs 4-5).
Schwartz provides direction on how to select the MWCO of the membrane, teaching that the membrane should have a MWCO that is 3 to 6 times lower than the target molecular weight. (page 7, paragraph 1). In addition, Schwartz teaches that diafiltration it is the process wherein smaller molecules are passed through the membrane while additional solvent is added at the same rate that a filtrate is generated. Diafiltration removes salts from the sample (i.e. desalting in instant claims 43-44), and one of ordinary skill in that art would have a reasonable expectation of success in using 10 DVs in a discontinuous diafiltration to achieve a 99.9% salt reduction (page 4, paragraphs 5-8 and Table 1). On the other hand, Schwartz also teaches that decreasing the amount of diafiltration solution used can represent a substantial savings in buffer and time (page 5, paragraph 1).
Millipore provides a hands-on guide to ultrafiltration/diafiltration optimization using Pellicon cassettes (page 1, paragraph 1). Millipore demonstrates the state of the art in optimization of ultrafiltration and teaches that optimization is needed to develop a robust process with consistent product yield and good quality. This optimization includes determining a TMP, concentration, and diafiltration volumes (page 1, paragraphs 1-2 and figure 1). Millipore teaches optimization of the TMP at the initial concentration (Part 1), and teaches that optimization of TMP for a 5 kDa membrane would begin at 10 psi (Part 1, step 3) and that the optimum TMP will depend on the feed flow rate (Part 1, calculations) and the results of the optimization data (figure 3). Regarding diafiltration volumes, Millipore teaches that there is a tradeoff between flux and diafiltration buffer volume (page 4, paragraph 13). Millipore teaches optimization of diafiltration volumes, indicating that the number of diavolumes may be chosen based on the product purity specifications. Millipore provides 7-12 diavolumes as an initial estimate for final formulation UF/DF steps (page 6, paragraph 4 and figure 6).
Gleich teaches that the initial concentration of the heparin is applied to filtration is 0.375 g/mL, determined from calculation of the disclosed initial concentration of 0.9 grams in 2.4 mL of solution. It would have been prima facie obvious to purify the high molecular weight heparin of Gleich by the tangential flow filtration of Xie using membranes with a MWCO selected using the teachings of Schwartz, to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the gel permeation method of purifying high molecular weight heparin taught by Gleich with the tangential flow filtration method of Xie, because Xie teaches that tangential flow filtration provides benefits of lower cost and higher efficiency as compared to gel permeation chromatography, and Schwartz provides teaching on how to select parameters for the application of tangential flow filtration to the heparin of Gleich. Considering the target 20 kDa MW of Gleich and the direction of Schwartz to select a membrane with a MWCO that is 3 to 6 times lower to use in tangential flow filtration, one of ordinary skill in the art prior to the effective filing date of the claimed invention would be motivated to optimize the MWCO of the membrane within the range of about 6.7-3.3 kDa, and thus have a reasonable expectation of success in optimizing the selected membrane for TFF to a MWCO of 5 kDa. One of ordinary skill in the art would have a reasonable expectation of success because Gleich teaches that any method of separation may be used.
Regarding the number of diafiltration volumes used, it would have been prima facie obvious to optimize the number of diafiltration volumes used because Millipore teaches that optimization, including optimization of diafiltration volumes, is needed to develop a robust process with consistent product yield and good quality. Furthermore, Schwartz teaches that decreasing the amount of diafiltration solution used can represent a substantial savings in buffer and time such that one of ordinary skill in the art would have been motivated to optimize the number of diavolumes in order to ensure that no unnecessary buffer or time is wasted in the filtration process. Millipore provides 7 – 12 diavolumes as an initial estimate for this optimization.
Regarding claim 39, Schwartz teaches that transmembrane pressure (TMP) is the force that drives fluid through the membrane, carrying along the permeable molecules (page 5, paragraph 3) and is an important variable in the TFF process (page 5, paragraph 2).
Regarding claim 40 as discussed above, 5 kDa MWCO membrane would be used in the TFF fractionation of the 20 kDa MW heparin of Gleich. Furthermore, Schwartz teaches that transmembrane pressure (TMP) is the force that drives fluid through the membrane, carrying along the permeable molecules (page 5, paragraph 3) and is an important variable in the TFF process (page 5, paragraph 2). The ability to monitor and control the pressure leads to more consistent results (paragraph bridging pages 5-6). It would have been prima facie obvious before the effective filing date of the claimed invention to select a TMP psi according to the optimization procedure of Millipore for the method of TFF fractionation taught by Gleich in view of Xie and Schwartz to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to optimize the psi because Schwartz teaches that TMP is an important variable in the TFF process, and Millipore teaches that the optimization is necessary to provide good product yield and quality.
Regarding claims 55-56, Xie teaches that the viscosity of polysaccharide can influence the ultrafiltration separation. If the viscosity of polysaccharides solution is very high, the membrane is easily fouled, whereas a low viscosity polysaccharide solution allowed for a good separation process. Thus Xie suggests that viscosity is dependent on the concentration (paragraph bridging pages 482-483). Thus Xie teaches that the concentration is a result effective variable, such that one or ordinary skill in the art would be motivated to optimize the initial sample concentration of 0.375 g/mL for gel filtration chromatography taught by Gleich to provide a method that is efficient while also preventing fouling of the membrane. Finally, the instant application does not demonstrate the critically of the ranges in claims 46 and 55-56 (see MPEP 2144(III)(A)). Thus, a prima facie case of obviousness exists.
Regarding claim 57, Xie teaches that the fractionation uses a hollow fiber membrane (page 480, paragraph 4).
Claims 36-37 and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Gleich et al. (WO 2021/163190; IDS 21/06/2023) in view of Xie et al. (Carbohyd. Polym., 2014; IDS 21/06/2023), Schwartz et al. (Pall Corp. bulletin, 2014; IDS filed 21/06/2023) and Millipore (Millipore application Note, 2008; PTO-892 03/28/2025), as applied to claims 34 and 46 above, further in view of Lormeau et al. (US RE35,770E; IDS filed 21/06/2023).
Gleich in view of Xie, Schwartz, and Millipore teaches as above. Furthermore, Schwartz teaches that the sample must be in fluid form to be subjected to TFF (figure 5 and page 5, paragraph 5).
The teachings of Gleich in view of Xie, Schwartz, and Millipore differ from that of the instantly claimed invention in that they do not teach the use of NaCl solution as the solvent for dissolving the heparin to be subjected to TFF.
Lormeau teaches that it is known in the art to fractionate heparin according to MW by methods such as gel filtration (col. 4, lines 40-45). Lormeau further teaches that it is useful to prepare a heparin solution comprising an NaCl solution as the solvent, wherein the concentration is 0.1 M (col. 12, lines 10-12). Thus Lormeau suggests dissolving heparin in a 0.1 M NaCl solution prior to fractionation by MW.
It would have been prima facie obvious to prepare a heparin sample dissolved in a 100 mM NaCl salt solution, as taught by Lormeau, for application in TFF as taught by Gleich in view of Xie and Schwartz to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to select the NaCl salt solution with a reasonable expectation of success because Lormeau teaches dissolving heparin in a 0.1 M NaCl solution prior to fractionation, and Schwartz teaches that the sample must be in fluid form to be subjected to TFF.
Claims 43-44 are rejected under 35 U.S.C. 103 as being unpatentable over Gleich et al. (WO 2021/163190; IDS 21/06/2023) in view of Xie et al. (Carbohyd. Polym., 2014; IDS filed 21/06/2023), Schwartz et al. (Pall Corp. bulletin, 2014; IDS 21/06/2023), and Millipore (Millipore application Note, 2008; PTO-892 03/28/2025), as applied to claim 34 above, further in view of Flengsrud (US 2011/0288283; IDS 21/06/2023).
Gleich in view of Xie, Schwartz, and Millipore teaches as above.
The teachings of Gleich in view of Xie, Schwartz, and Millipore differ from that of the instantly claimed invention in that they do not teach desalting the fractionated product by TFF using a desalting membrane.
Flengsrud teaches a method of producing glycosaminoglycan (claim 1) including purification though tangential flow filtration [0049]. Flengsrud further teaches that it is known in the art to desalt heparin products by TFF using a desalting membrane, and that the membrane may have a 1000 MWCO (Example 3 [0086]). Flengsrud teaches that desalting is particularly useful because it removes the salt and reduces the volume for further handling [0037], such as biological application [0082].
It would have been prima facie obvious before the effective filing date of the claimed invention to combine the method for fractionating heparin taught by Gleich in view of Xie and Schwartz with the method of desalting taught by Flengsrud to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to combine these prior art elements according to known methods to yield the predictable result of a fractionated and desalted heparin. Furthermore, Gleich teaches fractionated heparin for medicinal applications, and Flengsrud teaches that desalting a sample by TFF is beneficial to reduce volume and salt content before biological applications. One of ordinary skill in the art would have a reasonable expectation of success because both references teach the purification of glycosaminoglycans.
Claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over Gleich et al. (WO 2021/163190; IDS 21/06/2023), in view of Xie et al. (Carbohyd. Polym., 2014; IDS 21/06/2023), Schwartz et al. (Pall Corp. bulletin, 2014; IDS 21/06/2023), Millipore (Millipore application Note, 2008; PTO-892 03/28/2025), and Flengsrud (US 2011/0288283; IDS 21/06/2023) as applied to claims 34 and 43-44 above, further in view of Shriver et al. (US 8,609,632 B2; PTO-892 03/28/2025).
Gleich in view of Xie, Schwartz, and Millipore teaches as above. Gleich further teaches that the heparin composition may be administered by injection [0057], and that the heparin may be heparin sodium [0079].
The teachings of Gleich in view of Xie, Schwartz, and Millipore differ from that of the instantly claimed invention in that they do not teach sterilization using a submicron membrane.
Shriver discusses preparations and purifications of heparins for pharmaceutical applications. Shriver teaches that therapeutic compositions typically should be sterile and stable under the conditions of manufacture and storage (col. 38, lines 48-49), and that sterile injectable solutions can be prepared by incorporating the active compound (for example, heparin) in the required amount in an appropriate solvent followed by filtered sterilization (col. 38, lines 52-56). Shriver teaches sterilization of a heparin containing injection composition comprising filtration through 0.22 µm filters (col. 58, lines 60-64). Shriver further teaches that heparin sodium products are subject to degradation at very high temperatures and therefore cannot be terminally sterilized (col. 58, lines 36-38).
It would have been prima facie obvious before the effective filing date of the claimed invention to sterilize the heparin sodium product of the combined teachings of Gleich, Xie, Schwartz, and Flengsurd using the sterilization procedure of Shriver to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to include the sterilization process of Shriver in the method of the combined teachings of Gleich, Xie, Schwartz, and Flengsurd because a composition for injection should be sterile and Shriver teaches that heparin sodium cannot be subject to terminal sterilization but that a filtered sterilization procedure is suitable.
Claims 46-48 and 59 are rejected under 35 U.S.C. 103 as being unpatentable over Gleich et al. (WO 2021/163190; IDS 21/06/2023) in view of Xie et al. (Carbohyd. Polym., 2014; IDS 21/06/2023) and Schwartz et al. (Pall Corp. bulletin, 2014; IDS 21/06/2023).
Gleich teaches a method of treating a tissue comprising administering a fractionated heparin with an average molecular weight of about 20-40 kDa, where at least 50% of the heparin chains have a molecular weight of at least 20 kDa ([00153] and (claim 19). Gleich teaches that the methods of making high molecular weight heparin compositions can be carried out using any method known in the art for separating molecules of differing molecular weights, including fractionation by gel permeation chromatography [00177] of medicinal grade heparin, USP at an initial concentration of 0.9 grams in water to reach 2.4 mL of solution [00220]. Gleich further teaches that the heparin may be heparin sodium [00165].
Gleich does not teach that the heparin is separated by tangential flow filtration, the MWCO of the membrane, or the addition of diafiltration volumes.
Xie teaches that gel filtration chromatography is not only complicated but also expensive and that ultrafiltration membrane process has many advantages including low cost, energy savings, and high efficiency, and is used in the purification of polysaccharides (paragraph bridging pages 479-480). Xie teaches that the ultrafiltration is accomplished using tangential flow filtration (page 480, paragraph 4). Xie teaches that polysaccharides are separated by into fractions of varying MW using filters with different MW cut off (MWCO) values, which allow isolation of a target molecular weight (figure 2, and page 480, paragraphs 4-5).
Schwartz provides direction on how to select the MWCO of the membrane, teaching that the membrane should have a MWCO that is 3 to 6 times lower than the target molecular weight. (page 7, paragraph 1).
Gleich teaches that the initial concentration of the heparin is applied to filtration is 0.375 g/mL, determined from calculation of the disclosed initial concentration of 0.9 grams in 2.4 mL of solution. It would have been prima facie obvious to purify the high molecular weight heparin of Gleich by the tangential flow filtration of Xie using membranes with a MWCO selected using the teachings of Schwartz, to arrive at the instantly claimed invention., It would have been prima facie obvious for one of ordinary skill in the art to modify the gel permeation method of purifying high molecular weight heparin taught by Gleich with the tangential flow filtration method of Xie, because Xie teaches that tangential flow filtration provides benefits of lower cost and higher efficiency as compared to gel permeation chromatography, and Schwartz provides teaching on how to select parameters for the application of tangential flow filtration to the heparin of Gleich. Considering the target 20 kDa MW of Gleich and the direction of Schwartz to select a membrane with a MWCO that is 3 to 6 times lower to use in tangential flow filtration, one of ordinary skill in the art prior to the effective filing date of the claimed invention would be motivated to optimize the MWCO of the membrane within the range of about 6.7-3.3 kDa, and thus have a reasonable expectation of success in optimizing the selected membrane for TFF to a MWCO of 5 kDa. One of ordinary skill in the art would have a reasonable expectation of success because Gleich teaches that any method of separation may be used.
Regarding claim 46, Xie teaches that the viscosity of polysaccharide can influence the ultrafiltration separation. If the viscosity of polysaccharides solution is very high, the membrane is easily fouled, whereas a low viscosity polysaccharide solution allowed for a good separation process. Thus Xie suggests that viscosity is dependent on the concentration (paragraph bridging pages 482-483). Thus Xie teaches that the concentration is a result effective variable, such that one or ordinary skill in the art would be motivated to optimize the initial sample concentration of 0.375 g/mL for gel filtration chromatography taught by Gleich to provide a method that is efficient while also preventing fouling of the membrane. Finally, the instant application does not demonstrate the critically of the range in claim 46 (see MPEP 2144(III)(A)). Thus, a prima facie case of obviousness exists.
Regarding claim 59, Xie teaches that the fractionation uses a hollow fiber membrane (page 480, paragraph 4).
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Gleich et al. (WO 2021/163190; IDS 21/06/2023) in view of Xie et al. (Carbohyd. Polym., 2014; IDS 21/06/2023) and Schwartz et al. (Pall Corp. bulletin, 2014; IDS filed 21/06/2023), as applied to claim 46 above, further in view of Lormeau et al. (US RE35,770E; IDS filed 21/06/2023).
Gleich in view of Xie and Schwartz teaches as above. Furthermore, Schwartz teaches that the sample must be in fluid form to be subjected to TFF (figure 5 and page 5, paragraph 5).
Gleich in view of Xie and Schwartz does not teach the use of NaCl solution as the solvent for dissolving the heparin to be subjected to TFF.
Lormeau teaches that it is known in the art to fractionate heparin according to MW by methods such as gel filtration (col. 4, lines 40-45). Lormeau further teaches that it is useful to prepare a heparin solution comprising an NaCl solution as the solvent, wherein the concentration is 0.1 M (col. 12, lines 10-12). Thus Lormeau suggests dissolving heparin in a 0.1 M NaCl solution prior to fractionation by MW.
It would have been prima facie obvious to prepare a heparin sample dissolved in a 100 mM NaCl salt solution, as taught by Lormeau, for application in TFF as taught by Gleich in view of Xie and Schwartz to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to select the NaCl salt solution with a reasonable expectation of success because Lormeau teaches dissolving heparin in a 0.1 M NaCl solution prior to fractionation, and Schwartz teaches that the sample must be in fluid form to be subjected to TFF.
Claims 50-51, 53, and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Gleich et al. (WO 2021/163190; IDS 21/06/2023) in view of Xie et al. (Carbohyd. Polym., 2014; IDS 21/06/2023) and Schwartz et al. (Pall Corp. bulletin, 2014; IDS 21/06/2023), in view of Lormeau et al. (US RE35,770E; IDS 21/06/2023) as applied to claims 46 and 49 above, further in view of Millipore (Millipore application Note, 2008; PTO-892) and Hemavathi et al. (Biotechnology and Bioprocess Engineering, 2011; PTO-892).
Gleich in view of Xie and Schwartz in view of Lormeau teaches as above. As discussed above, 5 kDa MWCO membrane would be used in the TFF fractionation of the 20 kDa MW heparin of Gleich. Furthermore, Schwartz teaches that transmembrane pressure (TMP) is the force that drives fluid through the membrane, carrying along the permeable molecules (page 5, paragraph 3) and is an important variable in the TFF process (page 5, paragraph 2). The ability to monitor and control the pressure leads to more consistent results (paragraph bridging pages 5-6).
Gleich in view of Xie and Schwartz in view of Lormeau does not teach that the transmembrane pressure 10-15 psi.
Millipore demonstrates the state of the art in optimization of ultrafiltration and teaches that optimization is needed to develop a robust process with consistent product yield and good quality. This optimization includes determining a TMP, concentration, and diafiltration volumes (page 1, paragraphs 1-2). Millipore teaches optimization of the TMP at the initial concentration (Part 1), and teaches that optimization of TMP for a 5 kDa membrane would begin at 10 psi (Part 1, step 3) and that the optimum TMP will depend on the feed flow rate (Part 1, calculations) and the results of the optimization data (figure 3).
Thus Millipore suggests that this optimization would occur using Pellicon Cassettes, and Hemavathi teaches that these ultrafiltration membranes have a polyether sulfone membrane (page 3, paragraph 1). It would have been prima facie obvious before the effective filing date of the claimed invention to select a polyether sulfone membrane and a TMP psi according to the optimization procedure of Millipore for the method of TFF fractionation taught by Gleich in view of Xie, Schwartz, and Lormeau to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to optimize the psi because Schwartz teaches that TMP is an important variable in the TFF process, and Millipore teaches that the optimization is necessary to provide good product yield and quality.
Claim 52 is rejected under 35 U.S.C. 103 as being unpatentable over Gleich et al. (WO 2021/163190; IDS 21/06/2023), in view of Xie et al. (Carbohyd. Polym., 2014; IDS 21/06/2023), Schwartz et al. (Pall Corp. bulletin, 2014; IDS 21/06/2023), and Flengsrud (US 2011/0288283; IDS 21/06/2023) as applied to claim 46 above, further in view of Shriver et al. (US 8,609,632 B2; PTO-892).
Gleich in view of Xie and Schwartz teaches as above. Gleich further teaches that the heparin composition may be administered by injection [0057], and that the heparin may be heparin sodium [0079].
Gleich in view of Xie and Schwartz does not teach sterilization using a submicron membrane.
Shriver discusses preparations and purifications of heparins for pharmaceutical applications. Shriver teaches that therapeutic compositions typically should be sterile and stable under the conditions of manufacture and storage (col. 38, lines 48-49), and that sterile injectable solutions can be prepared by incorporating the active compound (for example, heparin) in the required amount in an appropriate solvent followed by filtered sterilization (col. 38, lines 52-56). Shriver teaches sterilization of a heparin containing injection composition comprising filtration through 0.22 µm filters (col. 58, lines 60-64). Shriver further teaches that heparin sodium products are subject to degradation at very high temperatures and therefore cannot be terminally sterilized (col. 58, lines 36-38).
It would have been prima facie obvious before the effective filing date of the claimed invention to sterilize the heparin sodium product of the combined teachings of Gleich, Xie, Schwartz, and Flengsurd using the sterilization procedure of Shriver to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to include the sterilization process of Shriver in the method of the combined teachings of Gleich , Xie, Schwartz, and Flengsurd because a composition for injection should be sterile and Shriver teaches that heparin sodium cannot be subject to terminal sterilization but that a filtered sterilization procedure is suitable.
Claim 58 is rejected under 35 U.S.C. 103 as being unpatentable over Gleich et al. (WO 2021/163190; IDS 21/06/2023) in view of Xie et al. (Carbohyd. Polym., 2014; IDS 21/06/2023), Schwartz et al. (Pall Corp. bulletin, 2014; IDS 21/06/2023) and Millipore (Millipore application Note, 2008; PTO-892 03/28/2025), as applied to claim 34 above, further in view of Hemavathi et al. (Biotechnology and Bioprocess Engineering, 2011; PTO-892 03/28/2025).
Gleich in view of Xie, Schwartz, and Millipore teaches as above.
The teachings of Gleich in view of Xie, Schwartz, and Millipore differ from that of the instantly claimed invention in that they do not teach the material of the fractionation membrane.
Thus Millipore suggests that optimization of ultrafiltration would occur using Pellicon Cassettes, and Hemavathi teaches that these ultrafiltration membranes have a polyether sulfone membrane (page 3, paragraph 1). Thus it would have been prima facie obvious before the effective filing date of the claimed invention to use Pellicon Cassettes, which have a polyether sulfone membrane, in the purification of the product in Gleich.
Response to Arguments
Applicant's arguments filed 09/26/2025 have been fully considered but they are not persuasive.
Insofar as Applicant’s arguments are applicable to the current rejections, Applicant argues that Millipore merely provides general guidance for optimization and not a teaching of the specific ranges of pressure and diafiltration volumes recited by the claims (page 9, paragraph 1, and paragraph bridging pages 9-10). This is not persuasive.
As discussed in the above grounds of rejection, absent any evidence to the contrary, the teachings of Schwartz and Millipore demonstrate the optimization of pressure and diafiltration volumes is routine and conventional in the art of tangential flow filtration. Millipore teaches that optimization of transmembrane pressure for a 5 kDa membrane would begin at 10 psi and that optimization of DVs would begin at 7-12 diavolumes. Thus the ranges of pressure and diafiltration volumes recited by the instant claims are prima facie obvious. MPEP 2144.05(II)(A) states that [W]here 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.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record with modifications made to account for the claim amendments filed 09/26/2025.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 34-40, 42-45, and 54-56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 11,712,447 B2 in view of Millipore (Millipore application Note, 2008; PTO-892 03/28/2025). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of ‘447 is directed to a method of manufacturing fractionated heparin comprising the same steps of dissolving and fractionating by tangential flow filtration using a fractionating membrane with an overlapping cutoff range of 8-12 kDa to achieve fractionated heparin of the same weight range (claim 1). ’447 additionally specifies USP heparin (claim 2), a NaCl solution of about 100 mM (claim 4), using a fractionation membrane with a MWCO of 10 kDa (claim 5), an applied pressure (claim 6), addition of diafiltration volumes (claim 8), desalting the fractionated heparin with a 3 kDa membrane (claim 11), and a sterilized heparin solution (claim 1). ‘447 does claim the process in which TFF fractionates the heparin to provide the desired molecular weight using a fractionation membrane with a MWCO which is between 8-12 kDa (claim 1), and thereby suggests that the MWCO effects the molecular weight of the fractionated heparin.
‘447 claims that the heparin is heparin sodium (claim 19). ‘447 claims that the NaCl solution has a concentration of about 100 mM (claim 22). ‘447 claims that the heparin is filtered through a 0.2 μm sterilization membrane (claim 18).
‘447 does not claim the process wherein the molecular weight cut off of the fractionation membrane is about 5 kDa (instant claim 38), the concentration of the heparin solution (claim 46, 55-56), the TMP (claims 40, 50), or the diafiltration volumes (claim 51).
Millipore provides a hands-on guide to ultrafiltration/diafiltration optimization using Pellicon cassettes (page 1, paragraph 1). Millipore demonstrates the state of the art in optimization of ultrafiltration and teaches that optimization is needed to develop a robust process with consistent product yield and good quality. This optimization includes determining a TMP, concentration, and diafiltration volumes (page 1, paragraphs 1-2 and figure 1). Millipore teaches optimization of the TMP at the initial concentration (Part 1), and teaches that optimization of TMP for a 5 kDa membrane would begin at 10 psi (Part 1, step 3) and that the optimum TMP will depend on the feed flow rate (Part 1, calculations) and the results of the optimization data (figure 3). Regarding diafiltration volumes, Millipore teaches that there is a tradeoff between flux and diafiltration buffer volume (page 4, paragraph 13). Millipore teaches optimization of diafiltration volumes, indicating that the number of diavolumes may be chosen based on the product purity specifications. Millipore provides 7 – 12 diavolumes as an initial estimate for final formulation UF/DF steps (page 6, paragraph 4 and figure 6).
Thus it would have been prima facie obvious before the effective filing date of the claimed invention to optimize the MWCO of the fractionation membrane within the claimed range of 8-12 kDa to achieve the result of the desired molecular weight of the fractionated heparin using a 5 kDa MWCO fractionation membrane. One of ordinary skill in the art would have had a reasonable expectation of success because ‘447 claims that the membrane will have a MWCO within the range of 8-12 kDa.
Regarding the number of diafiltration volumes used, it would have been prima facie obvious to optimize the number of diafiltration volumes used because Millipore teaches that optimization, including optimization of diafiltration volumes, is needed to develop a robust process with consistent product yield and good quality. Millipore provides 7-12 diavolumes as an initial estimate for this optimization.
Claims 46-53 and 60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 11,712,447 B2 further in view of Millipore (Millipore application Note, 2008; PTO-892) and Hemavathi et al. (Biotechnology and Bioprocess Engineering, 2011; PTO-892).
‘447 claims as above.
Regarding claims 47-48, ‘447 claims that the heparin is heparin sodium (claim 19).
Regarding claim 49, ‘447 claims that the NaCl solution has a concentration of about 100 mM (claim 22).
Regarding claim 52, ‘447 claims that the heparin is filtered through a 0.2 μm sterilization membrane (claim 18).
‘447 does not claim the concentration of the heparin solution (claim 46, 55-56), the TMP (claims 40, 50) the diafiltration volumes (claim 51), or the identity of the membrane as a PES membrane (58 and 60).
Millipore demonstrates the state of the art in optimization of ultrafiltration and teaches that optimization is needed to develop a robust process with consistent product yield and good quality. This optimization includes determining a TMP, concentration, and diafiltration volumes (page 1, paragraphs 1-2). Millipore teaches optimization of the TMP (Part 1), and teaches that optimization of TMP for a 5 kDa membrane would begin at 10 psi (Part 1, step 3) and that the optimum TMP will depend on the feed flow rate (Part 1, calculations) and the results of the optimization data (figure 3). Millipore also teaches that diafiltration volumes and concentration would be optimized for a TFF application (page 1, paragraph 2). In particular, the diafiltration volumes are suggested to be 7-12 as an initial estimate (Part 4, step 4), and the concentration of the material is dependent on the desired product concentration (Part 2).
Millipore teaches that this optimization would occur using Pellicon Cassettes, and Hemavathi teaches that these ultrafiltration membranes have a polyether sulfone membrane (page 3, paragraph 1).
It would have been prima facie obvious before the effective filing date of the claimed invention to select a polyether sulfone membrane and a TMP psi according to the optimization procedure of Millipore for the method of TFF fractionation claimed by ‘447 to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to select a polyether sulfone membrane as taught by Millipore, and to optimize the psi, concentration, and diafiltrations because Millipore teaches that the optimization is necessary to provide good product yield and quality.
Claims 57 and 59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 11,712,447 B2 in view of Millipore (Millipore application Note, 2008; PTO-892 03/28/2025), further in view of Hemavathi et al. (Biotechnology and Bioprocess Engineering, 2011; PTO-892 03/28/2025) as applied to claims 34 and 46 above, further in view of Xie et al (Carbohyd. Polym., 2014; IDS filed 21 June 2023).
‘447 in view of Millipore claims as above.
‘447 does not claim that the fractionation membrane is a hollow filter membrane.
Xie teaches fractionation using tangential flow filtration (page 480, paragraph 4). Xie teaches the separation of polysaccharides into fractions of varying MW using filters with different MW cut off (MWCO) values, which allow isolation of a target molecular weight, and teaches that the filters are a hollow fiber membrane (figure 2, and page 480, paragraphs 4-5).
It would have been prima facie obvious before the effective filing date of the claimed invention to exchange the PES membrane of Millipore in the method of ‘447 with the hollow fiber membrane of Xie to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to select a hollow fiber membrane for a method of fractionating heparin because both polyether sulfone membranes and hollow fiber membranes are recognized in the art to be useful as filters for TFF.
Claim 58 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 11,712,447 B2 in view of Millipore (Millipore application Note, 2008; PTO-892 03/28/2025) as applied to claim 34, further in view of Hemavathi et al. (Biotechnology and Bioprocess Engineering, 2011; PTO-892 03/28/2025).
‘447 in view of Millipore claims as above.
‘447 does not claim the identity of the membrane as a PES membrane (58 and 60).
As discussed above, Millipore suggests that optimization of ultrafiltration would occur using Pellicon Cassettes. Hemavathi teaches that these ultrafiltration membranes have a polyether sulfone membrane (page 3, paragraph 1). Thus it would have been prima facie obvious before the effective filing date of the claimed invention to use Pellicon Cassettes, which have a polyether sulfone membrane, in the purification of the product in Gleich.
Response to Arguments
Applicant's arguments filed 09/26/2025 have been fully considered but they are not persuasive. Insofar as Applicant’s arguments are applicable to the current rejections, Applicant argues that the ‘447 patent does not teach the specific diafiltration volume ranges recited by the amended claims (Remarks, page 12, paragraph 3). This is not persuasive.
As discussed in the above grounds of rejection, the teachings of Millipore demonstrate the optimization of diafiltration volumes is routine and conventional in the art of tangential flow filtration. Millipore teaches that optimization of DVs would begin at 7-12 diavolumes. Thus the ranges of diafiltration volumes recited by the instant claims are prima facie obvious. MPEP 2144.05(II)(A) states that [W]here 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.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record with modifications made to account for the claim amendments filed 09/26/2025.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/
Supervisory Patent Examiner, Art Unit 1693