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 .
Support for the amendments is within the instant application specification.
Applicant’s amendment to the claims filed on 9/2/2025 in response to the Non-Final Rejection mailed on 9/19/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
Claims 1-13, 15-21 are pending.
Claim 21 is newly added.
Claim 14 is cancelled.
Applicant’s notice of Appeal in response to the non-final office action dated 9/19/2025 is acknowledged and has been fully considered and is deemed persuasive to overcome at least one of the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Withdrawn Rejections
The rejection of claims 1-10, 12-13, 15-21 under 35 U.S.C. 103 as being unpatentable over Chowdhury et al. (2015, Avicenna Journal of Clinical Microbiology and Infection, 2(4): e31990, 24-29, cited on PTO-892 filed 5/21/2024) {herein Chowdhury} in view of Agilent Technologies (2017, cited on PTO-892 filed 5/21/2024) {herein Agilent} as evidenced by Lumen et al (2025, Lipids, Biology for Majors, cited on PTO-892 dated 6/2/2025) {herein Lumen} and Varanets et al (2017, Microbiology, cited on PTO-892 dated 6/2/2025) {herein Varanets} is withdrawn in view of Applicant’s amendment of claim 1 to recite ‘without using organic solvent’ and Applicant’s remarks within the Pre-Appeal Brief Conference Request dated 1/20/2026.
The rejection of claim 11 under 35 U.S.C. 103 as being unpatentable over Chowdhury et al. (2015, Avicenna Journal of Clinical Microbiology and Infection, 2(4): e31990, 24-29, cited on PTO-892 filed 5/21/2024) {herein Chowdhury} in view of Agilent Technologies (2017, cited on PTO-892 filed 5/21/2024) {herein Agilent} as applied to claims 1-10, 12-13, 15-21 and in further view of Inagawa (JP 2018035084A published on March 8, 2018 and filed on August 30, 2016, cited on PTO-892 filed 5/21/2024) {herein Inagawa} as evidenced by Lumen et al (2025, Lipids, Biology for Majors, cited on PTO-892 dated 6/2/2025) {herein Lumen} is withdrawn in view of Applicant’s amendment of claim 1 to recite ‘without using organic solvent’ and Applicant’s remarks within the Pre-Appeal Brief Conference Request dated 1/20/2026.
Maintained Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The rejection of claims 12-13, 15, 21 under 35 U.S.C. 101 is maintained for the reasons of record and the reasons set forth below because the claimed invention is directed to non-statutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because the claimed invention is a naturally occurring microorganism. The rejection has been modified in view of Applicant’s amendment of claim 12 to recite ‘5,000 to 20,000’ and newly added claim 21.
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
Yes, the claim is drawn to a composition of matter, which is one of the four statutory categories.
Step 2, Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes, the claim is directed to a natural phenomenon (product of nature). Said natural phenomenon is a naturally occurring component of gram negative bacteria, lipopolysaccharide.
Claims 12-13, 15, 21 are directed towards a lipopolysaccharide that is produced by the production method according to Claim 1, wherein the lipopolysaccharide is of a high purity, high content and low molecular weight lipopolysaccharide, and wherein the lipopolysaccharide is configured to activate an immune response in a subject in which the lipopolysaccharide is provided, wherein the low molecular weight is a molecular weight as measured by an SDS-PAGE method of 5,000 to 20,000 and wherein the lipopolysaccharide also contains a high molecular weight lipopolysaccharide with a molecular weight as measured by the SDS-PAGE method of more than 20,000 but not more than 100,000, wherein the content of the low molecular weight lipopolysaccharide with respect to a total amount of the low molecular weight lipopolysaccharide and the high molecular weight lipopolysaccharide is not less than 80%, and wherein the purity of the lipopolysaccharide is not less than 70 weight %.
Step 2, Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
Claim 12 includes additional elements of the lipopolysaccharide being of a high purity, high content and low molecular weight lipopolysaccharide, and wherein the lipopolysaccharide is configured to activate an immune response in a subject in which the lipopolysaccharide is provided, wherein the low molecular weight is a molecular weight as measured by an SDS-PAGE method of 5,000 to 20,000 and wherein the lipopolysaccharide also contains a high molecular weight lipopolysaccharide with a molecular weight as measured by the SDS-PAGE method of more than 20,000 but not more than 100,000, wherein the content of the low molecular weight lipopolysaccharide with respect to a total amount of the low molecular weight lipopolysaccharide and the high molecular weight lipopolysaccharide is not less than 80%, and wherein the purity of the lipopolysaccharide is not less than 70 weight %. Said limitations are naturally occurring properties of the LPS since it does not include any modifications of said LPS.
Claim 13 recites ‘is obtained from the gram-negative bacterium, wherein the gram-negative bacterium is at least one selected from the group consisting of a genus Escherichia, Salmonella, Pantoea, Acetobacter, Zymomonas, Xanthomonas, Enterobacter, Roseomonas, and Rhodobactor.’ As such, said LPS is naturally occurring without any significant modifications. Said characteristics are not sufficient to integrate into a practical application (MPEP 2106.05(f)-(g)).
Claim 15 includes additional elements of wherein a value (E/L ratio) obtained by dividing a lipopolysaccharide quantitative value (E) determined by an ELISA method by a lipopolysaccharide quantitative value (L) determined by a Limulus test (endpoint chromogenic method) is not more than 1.0. Such a limitation is native to the LPS. Therefore, it does not integrate the judicial exception into a practical application for the same reasons discussed above.
Claim 21 includes additional elements of wherein the low molecular weight is a molecular weight as measured by an SDS-PAGE method of 7,000 to 17,000, wherein the lipopolysaccharide also contains a high molecular weight lipopolysaccharide with a molecular weight as measured by the SDS-PAGE method of more than 25,000 but not more than 60,000, wherein the content of the low molecular weight lipopolysaccharide with respect to a total amount of the low molecular weight lipopolysaccharide and the high molecular weight lipopolysaccharide is not less than 80%. Said limitations are naturally occurring properties of the LPS since it does not include any modifications of said LPS.
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No. The judicial exception is recited without additional limitations amounting to significantly more than the exception. All of the signified additional elements to the judicial exception are considered to be native to the LPS which the judicial exception is to be performed as noted in Step 2A, Prong 2, and, therefore, do not amount to significantly more than the judicial exception that is claimed.
The instant Specification established that LPS in the instant Application is a naturally occurring product derived from the gram negative bacteria. Therefore it is understood that the extracted and purified LPS in this invention is identical to the naturally occurring LPS which is a product of nature. Thus, claims 12-13, 15, 21 encompass patent ineligible subject matter.
Consequently, it is understood that a LPS is necessarily a product of nature that has undergone purification to remove other chemical entities. In conclusion, a LPS does not correspond to a judicial exception of a product of nature.
As the instant claims recite judicial exceptions that are not integrated into practical application, and no elements that amount to significantly more than the judicial exception as recited, the claims were found not to be drawn to eligible subject matter under 35 U.S.C. 101.
RESPONSE TO REMARKS: Beginning on p. 2 of the Pre-Appeal Brief Conference Request, Applicants in summary contend that subjecting the LPS to hot water substantially changes the LPS, thereby rendering it non-naturally occurring.
This argument is found to be not persuasive. Examiner acknowledges and thanks Applicant for the reference regarding the stability of LPS at ‘low temperatures such as 70C.’ However, Examiner contends that simply subjecting the LPS to ‘hot water’ does not render the LPS non-naturally occurring as Applicant has shown that the LPS obtained still is a mixture of different molecular weight fractions. Just separating the natural product to different fractions does not render it eligible under 35 USC 101.
New 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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-13, 15-21 are rejected under 35 U.S.C. 103 as being unpatentable over Darveau et al (1983, Journal of Bacteriology, Examiner cited) {herein Darveau} in view of Agilent Technologies (2017, cited on PTO-892 filed 5/21/2024) {herein Agilent} as evidenced by Lumen et al (2025, Lipids, Biology for Majors, cited on PTO-892 dated 6/2/2025) {herein Lumen}. The new rejection is necessitated by Applicant’s amendment of claim 1 to recite ‘without using organic solvent’ and Applicant’s remarks within the Pre-Appeal Brief Conference Request dated 1/20/2026.
Claims 1-11, 16-20 are drawn to a lipopolysaccharide production method in which a lipopolysaccharide (LPS) is extracted without using organic solvent and purified from gram-negative bacterium, the lipopolysaccharide production method comprising: performing extraction from the gram-negative bacterium using hot water to obtain an extract liquid that contains the lipopolysaccharide, wherein performing extraction does not use organic solvent; and purifying the extract liquid or a solution containing the LPS in the extract liquid by using reverse-phase liquid chromatography to obtain the lipopolysaccharide, wherein a reverse-phase column used in the reverse-phase liquid chromatography has a packing material constituted of a material having a functional group of 1 to 8 carbons.
Claims 12-13, 15, 21 are drawn to a lipopolysaccharide that is produced by the production method according to Claim 1, wherein the lipopolysaccharide is of a high purity, high content and low molecular weight lipopolysaccharide, and wherein the lipopolysaccharide is configured to activate an immune response in a subject in which the lipopolysaccharide is provided, wherein the low molecular weight is a molecular weight as measured by an SDS-PAGE method of 5,000 to 20,000 and wherein the lipopolysaccharide also contains a high molecular weight lipopolysaccharide with a molecular weight as measured by the SDS-PAGE method of more than 20,000 but not more than 100,000, wherein the content of the low molecular weight lipopolysaccharide with respect to a total amount of the low molecular weight lipopolysaccharide and the high molecular weight lipopolysaccharide is not less than 80%, and wherein the purity of the lipopolysaccharide is not less than 70 weight %.
With respect to claims 1, 6-10, 13, Darveau teaches a method wherein LPS from Salmonella and Escherichia are isolated without using organic solvent (page 832, column 1, para 4; column 2, para 4). The method comprises suspending dried cells in Tris-hydrochloride buffer, RNase A and French pressing the cells twice (page 832, column 2, para 4). Subsequently, the suspension is incubated at 37C for 2hrs (page 832, column 2, para 4). Afterwards, tetraosodium EDTA, Tris-hydrochloride and SDS are added to the suspension (page 832, column 2, para 4). The sample is vortexed, centrifuged and incubated on a shaker at 37C overnight (page 832, column 2, para 4). Next, MgCl2 in ethanol is added and the sample is cooled to 0C (page 832, column 2, para 4). The pellet obtained is suspended in SDS-tetrasodium EDTA, Tris-hydrocholoride and sonicated (page 833, column 1, para 1). The solution is then incubated at 85C for 10-30min (page 833, column 1, para 1). The solution is centrifuge (page 833, column 1, para 2). Next, the pellet which contains LPS is resuspended in distilled water (page 833, column 1, para 2). The LPS is subsequently purified utilizing SDS-PAGE followed by Silver Staining (page 833, column 2, para 2).
With respect to claim 11, it would be obvious to one of ordinary skill in the art that the LPS produced by a gram-negative bacterium belonging to the genus Pantoea would be purified by the method taught by Darveau as Darveau teaches LPS is successfully extracted from gram negative bacteria without using organic solvent (page 832, column 1, para 4; column 2, para 4).
With respect to claim 12, it is noted that the recitation of “wherein the lipopolysaccharide is of a high purity, high content and low molecular weight lipopolysaccharide, and wherein the lipopolysaccharide is configured to activate an immune response in a subject in which the lipopolysaccharide is provided, wherein the low molecular weight is a molecular weight as measured by an SDS-PAGE method of 5,000 to 20,000 and wherein the lipopolysaccharide also contains a high molecular weight lipopolysaccharide with a molecular weight as measured by the SDS-PAGE method of more than 20,000 but not more than 100,000, wherein the content of the low molecular weight lipopolysaccharide with respect to a total amount of the low molecular weight lipopolysaccharide and the high molecular weight lipopolysaccharide is not less than 80%, and wherein the purity of the lipopolysaccharide is not less than 70 weight %” is a “product-by-process” claim limitation. MPEP 2113 states “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).” As such, the product obtained by Darveau would result in the same product as claimed. Nevertheless, Darveau teaches a method wherein LPS from Salmonella and Escherichia are isolated without using organic solvent (page 832, column 1, para 4; column 2, para 4).
With respect to claim 15, Examiner takes the position that the LPS taught by Darveau would inherently have the same characteristics as recited in claim 15 of a value (E/L ratio) obtained by dividing a lipopolysaccharide quantitative value (E) determined by an ELISA method by a lipopolysaccharide quantitative value (L) determined by a Limulus test (endpoint chromogenic method) is not more than 1.0 since Darveau teaches a method wherein LPS from Salmonella is isolated without using organic solvent (page 832, column 1, para 4; column 2, para 4), which is one of the microbial species recited within the instant application claim 13. Since the office does not have the facilities for examining and comparing Applicants’ LPS with the LPS of the prior art, the burden is on the Applicant to show a novel or unobvious difference between the claimed product and the product of the prior art (i.e., that the LPS of the prior art does not possess the same material structural and functional characteristics of the claimed LPS). See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594. ‘ However, given that Darveau teaches LPS from Salmonella, absent evidence otherwise, it is the Examiner’s position that the LPS taught by Darveau would necessarily have LPS with a value (E/L ratio) obtained by dividing a lipopolysaccharide quantitative value (E) determined by an ELISA method by a lipopolysaccharide quantitative value (L) determined by a Limulus test (endpoint chromogenic method) is not more than 1.0.
With respect to claims 19-20, Darveau teaches a method wherein the suspension is incubated at 37C for 2hrs (page 832, column 2, para 4). Absent evidence otherwise, it is the Examiner’s position that incubating the suspension at 37C for 2 hrs is within the first step of isolation of LPS without using organic solvent. Although the references of Darveau in view of Agilent do not explicitly teach the limitations of claims 19-20 (the first step is 50 to 150°C), MPEP 2144.05 states"[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (MPEP 2144.05 IIA)." One of ordinary skill would desire to optimize the temperature of the hot water depending on the particular application. It would be routine for one to arrive at the temperature for the application they intend on using the LPS. Therefore, the above invention would have been prima facie obvious.
However, Chen does not teach a second step of purifying the extract liquid or a solution containing the LPS in the extract liquid by using reverse-phase liquid chromatography to obtain the lipopolysaccharide, wherein a reverse-phase column used in the reverse-phase liquid chromatography has a packing material constituted of a material having a functional group of 1 to 8 carbons (claim 1). The lipopolysaccharide production method according to Claim 1, wherein the packing material is constituted of a material having a functional group of 2 to 6 carbons (claim 2). The lipopolysaccharide production method according to Claim 1, wherein the packing material is constituted of a material having a functional group of 2 to 4 carbons (claim 3). The lipopolysaccharide production method according to Claim 1, wherein the packing material is constituted of a material having a functional group of 4 carbons (claim 4). The lipopolysaccharide production method according to Claim 1, wherein the functional group is an alkyl group (claim 5). The lipopolysaccharide production method according to Claim 2, wherein the packing material is constituted of a material having a functional group of 2 to 4 carbons (claim 16). The lipopolysaccharide production method according to Claim 2, wherein the packing material is constituted of a material having a functional group of 4 carbons (claim 17). The lipopolysaccharide production method according to Claim 2, wherein the functional group is an alkyl group (claim 18).
With respect to claims 1-4, 16-18, Agilent teaches a method wherein reverse phase chromatography is used for the purification of macro molecules with nonpolar hydrocarbon chains (page 19). Evidentiary reference of Lumen is cited to demonstrate that lipids are hydrocarbons that are mostly nonpolar hydrophobic molecules (page 2, para 1). As such, it would be obvious to one of ordinary skill that reverse-phase chromatography could be used for the purification of LPS as LPS contains a hydrophobic lipid A region with nonpolar hydrocarbon chains. Furthermore, the silica gels in the column stationary phase are the packing material with the hydrocarbon chains between 1 and 18 carbon atoms as the functional group because they function to separate the mixture (page 19). Examiner is interpreting 1 to 8 carbons claimed by Applicant to encompass 1 to 18 carbons taught by Agilent. A prima facie case of obviousness exists where the claimed ranges and prior art ranges overlap, such as in the instant rejection. MPEP § 2144.05.
With respect to claims 5, 18, Agilent teaches a method wherein the packing material has an alkyl functional group (page 27).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to combine the teachings of Darveau and Agilent because Agilent teaches a method wherein reverse phase chromatography is used for the purification of macromolecules (page 47, para 2). While Darveau teaches a method wherein LPS from Salmonella and Escherichia are isolated without using organic solvent (page 832, column 1, para 4; column 2, para 4).
One of ordinary skill in the art would have had a reasonable expectation of success, a reasonable level of predictability, and would be motivated to combine the teachings of Darveau and Agilent because Agilent provides the motivation for Darveau to substitute the purification of LPS taught by Darveau with reverse phase chromatography, taught by Agilent, since Agilent establishes that the packed column in reverse liquid chromatography with the alkyl functional group is successful for the purification of macro molecules with nonpolar hydrocarbon chains, of which is a property of LPS (page 19). In addition, Darveau would be motivated to substitute reverse-based chromatography for SDS-PAGE and Silver Staining for the analysis/characterization of LPS as utilizing reverse-phase chromatography would allow Darveau to achieve high sensitivity and quantitative analysis of LPS, with minimal artifacts. Thereby utilizing the purification method taught by Agilent would allow Darveau to better analyze the endotoxin obtained from the bacterium. MPEP 2143.I.B states “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.” Additionally, substituting the SDS-PAGE and silver staining with the reverse-phase chromatography would provide a more time-efficient method of the detection and characterization of the endotoxin taught by Darveau. One of skill in the art would have a reasonable expectation of success to make and use the claimed LPS extraction and purification method because Darveau provides the basic method for extracting LPS and its uses and methods of making it. Agilent provides the steps of reverse-phase liquid chromatography for the purification of macromolecules with nonpolar hydrocarbons for optimized resolution.
One of ordinary skill in the art would be motivated to combine the teachings of Darveau and Agilent because doing so would produce isolated and purified LPS at higher concentrations with less artifacts (contaminants). Furthermore, the extraction method taught by Darveau is routinely done within the art, since 1983 (date of the art), therefore the supplies for the method are widely available. As such, one of skill in the art would be motivated to utilize said methods for the isolation and purification of LPS. Therefore there would be a reasonable expectation of success to arrive at the above invention. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
RESPONSE TO REMARKS: This argument is found to be moot in view of the new rejection. Examiner contends that Darveau teaches a method wherein LPS is isolated from bacteria without using organic solvent (abstract). Agilent provides the motivation for Darveau to substitute reverse-based chromatography for SDS-PAGE and Silver Staining for the purification of LPS as utilizing reverse-phase chromatography would allow Darveau to achieve higher sensitivity, better quantitative analysis, thereby allowing for Darveau to better analyze the LPS obtained from bacteria.
Conclusion
Status of the claims:
Claims 1-13, 15-21 are pending.
Claim 14 is cancelled.
Claims 1-13, 15-21 are rejected.
No claims are in condition for allowance.
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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERICA NICOLE JONES-FOSTER whose telephone number is (571)270-0360. The examiner can normally be reached mf 7:30a - 4:30p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERICA NICOLE JONES-FOSTER/ Examiner, Art Unit 1656
/MANJUNATH N RAO/ Supervisory Patent Examiner, Art Unit 1656
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