DETAILED ACTION
The present application is a continuation-in-part of PCT/ES2020/070695, filed 10 November 2020; and a continuation-in-part of PCT/ES2020/070271, filed 27 April 2020.
The preliminary amendment filed 07 July 2025 is acknowledged. As requested, the supplemental amendment, submitted 27 August 2025, placing the dependent claims in order after the claim from which it depends is acknowledged.
Claims 51-76 are pending in the current application. Claims 54 and 55 are withdrawn as being drawn to a non-elected invention, see below. Claims 51-53 and 56-76 are examined on the merits herein.
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 .
Election/Restrictions
On 14 May 2025, a restriction requirement was made between Group I, a process for preparing a LMWH; Group II, another process for preparing LMWH; Group III, a LMWH product; and Group IV, a method of treating or preventing a condition that is therapeutically response to LMWH.
On 27 August 2025, Applicant submitted a supplemental preliminary amendment, such that the claims corresponding to new Group I are now product-by-process claims; the claims corresponding to new Group II are product-by-process claims; Group III is still a LMWH product; and Group IV is still drawn to method of treating or preventing a condition that is therapeutically response to LMWH.
Applicant's election with traverse of Group I in the reply filed on 07 July 2025 is acknowledged. Upon searching the limitations of Group I, the restriction requirement between newly submitted claims corresponding to new Group I, new Group II and Group III are withdrawn. New groups I-III will be examined together.
It is respectfully noted, Group IV is withdrawn as being drawn to a non-elected invention. Furthermore, since Applicant has amended the process for preparing to product-by-process claims, and will now receive an action on the merits directed to product-by-process claims, any claims presented in any future amendment drawn to a process for preparing will be withdrawn as being drawn to a non-elected invention.
The traversal is on the ground(s) that there is no undue burden searching the method of use of Group IV, because it necessarily employs the LMWH of Group III. This is not found persuasive because a search of Group IV not only requires searching active steps and patient populations, but it also poses a serious examination burden because a search of Group IV is likely to raise serious examination issues, such as under 35 U.S.C. §112(a) .
The requirement is still deemed proper and is therefore made FINAL.
Claims 54 and 55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 07 July 2025.
Claim Objections
Claims 51-53 and 56-76 are objected to because of the following informalities: the claims recite “mol” and “mol.”. It is respectfully requested the claims be amended to recite “mol” without the period. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 52, 53, 59, 60, 61, 63, 66 and 72 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 52 and 53 depend from canceled claim 50. Claim 60 depends from canceled claim 26. Thus, the metes and bounds of the claims are indefinite.
The recitation “for a period of at least about 8 h” in claim 59 renders the claims herein indefinite. The recitation “about 8 h” could mean “7.5 h,” but then “at least” would suggest that it does not include “7.5 h”. Thus, the recitation “at least about 8 h” suggests conflicting boundaries.
The Applicant is requested to note that the Federal Circuit in Amgen, Inc. v. Chugai, 927 F.2d at 1200, 1218 (Fed. Cir. 1991), held that a word of degree can be indefinite when it fails to distinguish the invention over the prior art and does not permit one of ordinary skill to know what activity constitutes infringement. The recitation “at least about 160,000” has been held indefinite. Id. at 1203.
The following are similarly indefinite: “for at least about 3 h at a temperature of at least about 20°C” (claim 59); “at least about 24 hours” (claim 60); “at least about 80 IU/mg”; “at least about 5 IU/mg” (claims 61, 63, 66, 72);
The recitation “molar ratio…in the range of about 3-6% w/v” in claim 60 renders the claim herein indefinite. A ratio is usually a unitless value, not expressed as a percentage. Appropriate correction is respectfully requested.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 51, 56-61 and 65-76 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Rodriguez et al. (WO2014020227, cited in PTO-892).
Rodriguez et al. disclose preparing a LMWH from BEMP, having an average MW of 3,534 Da, an anti-FXa activity of 125.2 IU/mg, an anti-FIIa activity of 19.4 IU/mg (example 3). BEMP is 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3-diaza-2-phosphorine (para [0022]).
Rodriguez et al. disclose preparing a LMWH from TTMG, having an average MW of 3,704 Da, an anti-FXa activity of 118.5 IU/mg, an anti-FIIa activity of 16.2 IU/mg (example 3). TTMG is 2-tert-butyl-1,1,3,3-tetramethylguanidine (para [0022]).
The LMW of example 3 was prepared from example 2 (having an average MW of 2,787 Da, an anti-FXa activity of 121.5 IU/mg and an anti-FIIa activity of 8.2 IU/mg), wherein the LMWH was redissolved in water, sodium chloride was added to a concentration of 10% w/v, precipitated with methanol (para [0061]). The precipitate was filtered, washed with methanol, and dried in vacuo. Thus, Rodriguez et al. disclose purifying heparin two times gave a product with a higher average MW, similar anti-FXa activity, and higher anti-FIIa activity.
The LMWH of example 3 was prepared from the LMWH heparin prepared from example 2. 50 g sodium heparin was dissolved in 365 mL water (about 14% w/v), to which a 50% w/v aqueous solution of benzalkonium chloride was added (assumed standard room temperature since no temperature conditions were described). The product was filtered, washed with water and lyophilized to give benzalkonium heparinate. The benzalkonium heparinate was then dissolved in CH2Cl2 and heated to 35 °C. Three portions of base, BEMP, was added and reacted at 35 °C for 8 hours, 16 hours and then 8 hours (time of reaction after each portion of base was added). To this, hydrogen peroxide was added, and the reaction maintained for 16 h at 35 °C. The weight: volume ratio between benzalkonium heparinate and hydrogen peroxide is between 1:1 and 1:0.01 (claim 8). The LMWH was precipitated from a solution of sodium acetate in methanol. The precipitate was collected, washed with methanol, neutralized with sodium chloride to a concentration of 10% w/v, and precipitated with methanol. The precipitate was collected by filtration, washed with methanol and dried in vacuo.
In example 4, the BEMP base was replaced with Triton B. Here, three portions of triton B were added, and reacted at 35 °C for 8 hours, 16 hours and then 8 hours. Subsequently, hydrogen peroxide was added to the solution. The product had an average MW of 2387 Da, an anti-FXa activity of 94 IU/mg (para [0082]). When BEMP was used, the average MW was 2787 Da, and the product had an anti-FXa activity of 121.5 IU/mg. BEMP conferred greater selectivity in the depolymerization reaction, with greater preservation of the ATIII activating pentasaccharide, as evidenced by the higher anti-FXa activity (para [0110]).
The present claims are product-by-process claims. See MPEP 2113(I), “"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself.”. Also MPEP 2113 (II), “"The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature" than when a product is claimed in the conventional fashion.”.
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433.
While claim 51 is directed towards a LMWH prepared from specific H2O2 reaction conditions not expressly disclosed by Rodriguez et al., it appears the LMWH prepared by Rodriguez et al. is the same as a LMWH prepared by the process steps of claim 51.
According to the present Specification, the step of treating benzalkonium heparinate with H2O2 is performed at a temperature of at least about 20 °C, for at least about three hours (see para [0044]). In example 1, the reaction was performed at 30±5 °C for more than 3 hours (preferably about 14-18 hours), (para [0114]). And if the claimed amounts of heparin and H2O2 were converted to a weight to volume ratio, the ratio would be 1:1 to 1:0.04 (assuming 1 kg heparin, and 0.04-1L H2O2).
Rodriguez et al. describe preparing LMWH with a step of removing impurities using H2O2. Rodriguez et al. teach, H2O2 was added to depolymerized heparin salt, and the reaction maintained for 16 h at 35 °C. The weight: volume ratio between benzalkonium heparinate and H2O2 is between 1:1 and 1:0.01. Thus, Rodriguez et al. teach treating depolymerized heparin salt at a temperature of 35 °C, which is at least about 20 °C, and the same temperature used in Example 1 of the present Specification. Additionally, Rodriguez et al. teach performing the reaction for 16 hours, which lies within the range of the preferred amount of time described in the present Specification. Finally, Rodriguez et al. teach treating depolymerized heparin salt with H2O2 at a weight to volume ratio that significantly overlaps with the ratio of claimed ingredients.
The claims recite the prepared LMWH have an average MW of 3,000-3,8000 Da. The claims recite the LMWH exhibits an anti-FXa activity of at least about 80 IU/mg, or in the range of about 80-120 IU/mg or about 95-120 IU/mg. The claims also recite the LMWH exhibits an anti-FIIa activity of at least about 5 IU/mg or in the range of about 5-20 IU/mg, or about 10-20 IU/mg.
Rodriguez et al. disclose the LMWH obtained from the aforementioned method using BEMP had an average MW of 3,534 Da, an anti-FXa activity of 125.2 IU/mg, an anti-FIIa activity of 19.4 IU/mg (example 3). LMWH from TTMG, had an average MW of 3,704 Da, an anti-FXa activity of 118.5 IU/mg, an anti-FIIa activity of 16.2 IU/mg (example 3). TTMG is 2-tert-butyl-1,1,3,3-tetramethylguanidine (para [0022]).
The average MW of the LMWH of Rodriguez lies within the range of claim 52. It also has the same/similar anti-FXa and anti-FIIa properties recited in claims 61, 66 and 72.
Since the Office does not have the facilities for preparing the claimed materials and comparing them with prior art inventions, the burden is shifted to Applicant to show a novel or unobvious difference between the claimed product and the product of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980), see MPEP 2112.
Thus, the disclosure of Rodriguez et al. anticipates present claims 51, 56-61 and 65-76.
Claim(s) 51, 53, 56-61 and 65-76 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xu et al. (CN102399379, cited in PTO-892).
Xu et al. is directed towards preparing a low molecular weight heparin product (LMWH), having a weight average MW of 1500 to 4200 Daltons (para [0012]). Xu et al. teach a pharmaceutical composition comprising the LMWH and a pharmaceutically acceptable carrier (para [0042]). The LMWH has an anti-factor Xa of 100-150 IU/mg; anti-factor IIa of 0.001-10 IU/mg or 0.01-10 IU/mg (para [0020], [0045]).
Generally, Xu et al. teach (a) depolymerizing heparin quaternary ammonium salt, dissolved in CH2Cl2 with a quaternary ammonium base (para [0027], [0047], [0049]). The base is preferably benzyltrimethylammonium hydroxide (para [0031]). The temperature can range from 5-80 °C, and for 1-10 days (i.e. at least about 8 h, per claim 59, a), (para [0050]). The depolymerized heparin can be converted to a sodium salt (para [0057]). The depolymerized heparin can be separated and purified by conventional methods including alcohol precipitation, and can be decolorized and impurities removed with hydrogen peroxide (para [0033], [0051]).
To an aqueous solution of benzethonium chloride was added a solution of heparin sodium in water to form benzethoxyammonium heparinate precipitate (Example 1, para [0072]). The precipitate was filtered to obtain a filter cake, washed with water and then dried to give a dry salt. The benzethoxyammonium heparinate was dissolved in CH2Cl2, to which 40% w/v benzyltrimethylammonium hydroxide in methanol (Triton B) was added, and heated to 25 °C and reacted for 168 hours (para [0076]). A solution of sodium acetate in methanol was added, thereby precipitating the LMWH heparin as a LMWH sodium salt, which was washed with methanol and dried in vacuo to obtain a light yellow LMWH salt (para [0077]). The heparin (2.1g) was then treated with aqueous sodium hydroxide at pH 8.4 (para [0079]). In example 5, the LMWH salt was purified with 33% hydrogen peroxide (210 µL), stirred for 2 hours (para [0111]). After standing for 30 minutes, sodium chloride was added to increase the salt concentration to 10%, methanol was added to precipitate the LMWH salt, which was then washed with methanol and vacuum dried. The dried product was further purified by a gel column, where products with a MW below 5,000 Da were collected and lyophilized to obtain a purified LMWH.
The teaching above of treating 2.1 g LMWH salt with 210 µL of a 33% H2O2 solution is equivalent to treating depolymerized heparin with about 0.1 L H2O2, that is 33% w/v in water, per kg heparin salt.
The present claims are product-by-process claims. See MPEP 2113(I), “"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself.”. Also MPEP 2113 (II), “"The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature" than when a product is claimed in the conventional fashion.”.
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433.
Claim 51 is directed towards a LMWH prepared from specific H2O2 reaction conditions expressly disclosed by Xu et al. Thus, it appears the LMWH prepared by Xu et al. is the same as a LMWH prepared by the process steps of claim 51.
Claims 56, 69 and 73 specify the reaction with H2O2 is performed at 20-50 °C for a period of at least 3 h.
Xu et al. do not expressly disclose the temperature, thus it can be assumed the reaction was performed at room temperature, i.e. about 20-25 °C. Furthermore, Xu et al. describe stirring the reagents for 2 hours, and then letting it sit for a further 30 min. Thus, Xu et al. describe reacting for 2.5 hours, which is similar to the 3 hours recited in the product-by-process claims. It is expected reacting depolymerized heparin with H2O2 for 2.5 hours will give the same or similar product as reacting for 3 hours, especially all other things being the same.
As noted above, the teaching above of treating 2.1 g LMWH salt with 210 µL of a 33% H2O2 solution is equivalent to treating depolymerized heparin with about 0.1 L H2O2, that is 33% w/v in water, per kg heparin salt. Thus, the weight to volume ratio of heparin salt and H2O2 is 1:0.1.
The claims recite the prepared LMWH have an average MW of 3,000-3,8000 Da. The claims recite the LMWH exhibits an anti-FXa activity of at least about 80 IU/mg, or in the range of about 80-120 IU/mg or about 95-120 IU/mg. The claims also recite the LMWH exhibits an anti-FIIa activity of at least about 5 IU/mg or in the range of about 5-20 IU/mg, or about 10-20 IU/mg.
Xu et al. is directed towards preparing a low molecular weight heparin product (LMWH), having a weight average MW of 1500 to 4200 Daltons (para [0012]). The LMWH has an anti-factor FXa of 100-150 IU/mg; anti-factor IIa of 0.001-10 IU/mg or 0.01-10 IU/mg (para [0020], [0045]). The average MW of the LMWH of Rodriguez encompasses the ranges claimed. It also has the same/similar anti-FXa and anti-FIIa properties recited in claims 61, 66 and 72.
Since the Office does not have the facilities for preparing the claimed materials and comparing them with prior art inventions, the burden is shifted to Applicant to show a novel or unobvious difference between the claimed product and the product of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980), see MPEP 2112.
Thus, the disclosure of Xu et al. anticipates claims 51, 53, 56-61 and 65-76 of the present application.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 51-53 and 56-76 are rejected under 35 U.S.C. 103 as being unpatentable over Rodriguez et al. in view of Jeske et al. (Blood, 2004, vol. 104, no. 11, cited in PTO-892), and Guan et al. (Journal of Pharmaceutical Sciences, 2016, vol. 105, pp. 1843-1850, cited in PTO-892).
Rodriguez et al. teach as discussed above.
Rodriguez et al. do not expressly disclose a 1,6-anhydro residue content of about 1-15% at the reducing terminus; the molar ratio of 1,6-anhydroglucosamine (1,6-anG) residues to 1,6-anhydromannosamine (1,6-anM) residues; mol% of 1,6-anG or 1,6-anM (present claims 52, 62-64).
Jeske et al. teach heparin cleave under alkaline conditions produces LMWH, having 1,6-anhydromannosamine and/or 1,6-anhydroglucosamine at the reducing end (abstract). Jeske et al. teach altering the temperature and pH of the depolymerization of heparin under alkaline conditions produces 0, 5, 10, 20 or 40% 1,6-anhydrosugar (Materials or Methods). No effect on anticoagulant or antiprotease activity was observed when the 1,6-anhydro content varied between 0 and 10% (Results). When the 1,6-anhydro content was increased to 20 and 40%, a content-dependent reduction in anticoagulant activity was observed, such that the prolongation of the APTT and Heptest by the 40% 1,6-anhydro LMWH was 58 and 23% less, respectively than that produced by the LMWH lacking the 1,6-anhydro group. Inhibition of thrombin activity was 35% lower with the 40%-anhydro LMWH compared to the 0% anhydro activity. Anti-Xa activity was 7% lower with the 40%-anhydro LMWH compared to the 0% anhydro.
Guan et al. teach preparing LMWH like enoxaparin from bovine lung (to give bovine lung heparin-derived enoxaparin) and porcine intestine (to give porcine intestine heparin-derived enoxaparin), (abstract). Guan et al. teach enoxaparin is prepared by benzylation and alkaline depolymerization from porcine intestine, and is prevalent in the anticoagulant drug market. Guan et al. teach varying alkaline concentration and temperature conditions during the depolymerization reaction (Table 1). Guan et al. found bovine lung heparin-derived enoxaparin (BLE) treated with 3.5 g/L sodium hydroxide (instead of 4.0 g/L), and at 50 °C, gave a product not having any 1,6-anhydroderivative, when the reaction was performed for 2 hours (BLE-b). 1,6-anhydro derivatives were detected when the BLE was depolymerized under those same conditions, but for 6 hours (BLE-1, BLE-2, BLE-3). The BLEavg number average molecular weight (Mn) was 3795 ± 62 Da, and the BLEavg average molecular weight (Mw) was 4604 ± 59 Da (Table 2). Guan et al. teach the bovine lung heparin-derived enoxaparin mainly contain 1,6-anhydroglucopyranose, whereas in porcine intestine heparin-derived enoxaparin) (PIE), the amounts of 1,6-anhydroglucopyranose and 1,6-anhydromannopyranose were approximately equal (p.1849, NMR Spectroscopy; and figure 3b and 3c).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare a LMWH having a less than 15% 1,6-anhydro residues, because Jeske et al. found LMWH having 0-10% 1,6-anhydro content had higher anticoagulant activity, and higher anti-Xa activity than LMWH having 20-40% 1,6-anhydro content.
From the combined teaching of Jeske et al. and Guan et al., the ordinary artisan would have known 1,6-anhydro content can be modified by optimizing the temperature and pH conditions during depolymerization of heparin. Guan et al. further demonstrate lowering the temperature, pH and reaction time produces heparin with 0-10% 1,6-anhydrosugars.
The ordinary artisan would have been motivated to prepare LMWH having about 1:1 1,6-anA to 1,6-anM or greater than 1:1, because Guan et al. teach LMWH derived from porcine has about an equal amount of 1,6-anG to 1,6-anM, whereas LMWH derived from bovine lung had a greater amount of 1,6-anA to 1,6-anM.
One having ordinary skill in the art would have been motivated to prepare a pharmaceutical composition comprising LMWH having a MW of about 3000-3800 Da, because Rodriguez et al. found they had improved anti-FXa and anti-FIIa activity compared to LMWH of the prior art. The ordinary artisan would have been motivated to formulate the LMWH with a pharmaceutically acceptable carrier, because heparin and LMWH are known to be used as part of anticoagulation therapy.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Claim(s) 51-53 and 56-76 are rejected under 35 U.S.C. 103 as being unpatentable over Rodriguez et al. (cited above) in view of Xu et al. (cited above), and further in view of Jeske et al. (cited above) and Guan et al. (cited above).
Rodriguez et al. teach as discussed above. While Rodriguez et al. teach preparing LMWH from Triton B, Rodriguez et al. do not expressly disclose preparing LMWH having a Mw of 3-3.8 kDa and prepared from Triton B.
Xu et al. teach as discussed above.
Jeske et al. teach as discussed above.
Guan et al. teach as discussed above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare LMWH having a Mw of 3-3.8 kDa and from Triton B.
Rodriguez et al. teach reacting heparin salt with three portions of Triton B at 35 °C, and reacting for 8 hours, then 16 hours and an additional 8 hours. However, LMWH obtained from this method had a Mw of 2,387 Da, and an anti-FXa activity of 94 IU/mg.
Xu et al. teach treating heparin salt with 40% w/v triton B, heating to 25 °C and reacting for 168 hours. Xu et al. is directed towards preparing low molecular weight heparin product (LMWH), having a weight average MW of 1500 to 4200 Daltons (para [0012]). The LMWH has an anti-factor Xa of 100-150 IU/mg; anti-factor IIa of 0.001-10 IU/mg or 0.01-10 IU/mg (para [0020], [0045]).
While Rodriguez et al. teach optimized reaction conditions for bases other than Triton B, the ordinary artisan would have known from the combined teaching of Rodriguez et al., Jeske et al. and Guan et al., alkalinity and reaction time affects the depolymerization reaction. LMWH products obtained from varying the aforementioned conditions have measurable differences in MW, 1,6-anhydro content, anti-FIIa and anti-FXa activity. The prior art as a whole demonstrates MW, 1,6-anhydro content, anti-FIIa and anti-FXa activity are result effective variables, and specifically temperature, alkalinity and reaction time affects the depolymerization reaction.
While Rodriguez et al. teach depolymerizing at 35 °C for 8 hours, then 16 hours and then 8 hours was optimal for BEMP and TTMG, Xu et al. teach depolymerizing with Triton B at 25 °C. Xu et al. further teach the reaction conditions can be varied. The temperature can range from 5-80 °C, and the depolymerization should last for at least about 8 hours, or anywhere between 1-10 days.
From Jeske et al. and Guan et al., the ordinary artisan would have generally known lower temperature, lower alkalinity, and shorter reaction time for the depolymerization step gave a more homogenous product, having higher Mw, lower 1,6-anhydro content, higher anti-FIIa and higher anti-FXa.
See MPEP 2144.05 (II), “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”. The ordinary artisan would have been motivated to use Triton B during the depolymerization reaction, and prepare a LMWH having the same MW as the LMWH of Rodriguez et al. because they had a narrow average MW, high anti-FIIa activity and high anti-FXa activity.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699