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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on October 29, 2025 has been entered.
Priority
This application is a 371 of PCT/IB2020/051430 02/20/2020 which claims benefit of provisional application 62/808,907 02/22/2019.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 10/29/2025 has been considered.
Claim Status
The claim set and Applicant’s remarks filed on October 29, 2025 have been entered. Claims 2 and 6-27 are canceled. Thus, claims 1, 3-5 and 28-43 as amended are examined on the merits herein.
Response to Arguments
(I) The rejection of claims 1, 3-5 and 28-43 under 35 U.S.C. 103; and
(II) The provisional rejection of claims 1, 3-5 and 28-43 on the ground of nonstatutory double patenting are maintained.
Applicant argues:
(A) Seal’s method of flocculation, as it was actually carried out, could not have separated capsular polysaccharides from contaminants (such as proteins) as required by the claims, see Applicant’s arguments, pg. 6, paragraph 2.
(B) Seal never mentions purifying polysaccharides and never tested whether polysaccharides of any kind was present at all in either the flocculated material or supernatant produced in the course of its experiments. Therefore, even if a person of ordinary skill were to have consulted Seal for some reason, they would have gained no guidance whatsoever whether adding a flocculating agent, such as alum, to a solution of bacterial capsular polysaccharide would be effective; and there is no way to predict whether, after adding the alum, bacterial capsular polysaccharide would end up in the liquid, as opposed to being trapped in the flocculated material along with the contaminants, see Applicant’s arguments, pg. 6, paragraph 3,
(C) The Office action does not explain how a person of ordinary skill in the art knowing that Seal’s bacterial preparations contained no capsular polysaccharide, could have predicted alum’s ability to separate bacterial proteins (contaminant) from polysaccharides by trapping the former in flocculated material but not the latter, see Applicant’s arguments, pg. 7, paragraph 1.
(D) A person of ordinary skill in the art knowing Seal’s C. diphtheria bacteria lacked a polysaccharide capsule would have no idea if Seal’s method could be effective to separate bacterial capsular polysaccharides from proteins, see Applicant’s arguments, pg. 7, paragraph 2.
(E) The Office action did not explain where a motivation to combine Han and Seal could have arisen as the lack of predictability of Seal’s methods if tried with bacteria which do produce a capsule (such as S. pneumoniae) would have been effective to sequester contaminants within flocculated material while capsular polysaccharide remained in the supernatant also eliminates any possibility of their having been a reasonable expectation of success, Applicant’s arguments, pg. 7, paragraph 2.
(F) With respect to rejection (II), the provisional obviousness double patenting (ODP) rejection of U.S. Appl’ 17/799,992, the Applicant argues the instant claims were filed earlier than the asserted reference claims, therefore the instant claims cannot be invalidated for ODP by any of the later filed claims co-pending in U.S. Patent Application No. 17/799,992, see Applicant’s arguments, pg. 10, paragraph 1.
With respect to Applicant’s arguments (A)-(E), the Examiner respectfully notes the 103 rejection maintained below has been modified to include the Chatel reference which teaches that it is a known consideration within the prior art to use chemical flocculants such as aluminum sulphate after microbial cell broths are mechanically or chemically lysed for purification purposes.
Additionally, as evidence by Wu, Wu discloses multivalent pneumococcal conjugate vaccine (PVC) antigens are bound to the aluminum adjuvant (alum) in the vaccine through CRM197-alum interactions; and wherein unconjugated polysaccharide species are not bound to the aluminum adjuvant.
One of ordinary skill in the art would have been motivated to purify S. pneumoniae serotype 15B capsular polysaccharide from the fermentation culture, by specifically removing bacterial cell proteins of S. pneumoniae before conjugation to a carrier protein, specifically conjugating to CRM197 as taught by Han, in order to minimize impurities and therefore adverse side effects from administering a S. pneumoniae vaccine containing bacterial cell proteins of S. pneumoniae.
The Examiner also respectfully notes Chatel teach the use of aluminum sulphate as a flocculating agent within microbial cell harvests for clarification after bacterial cells are lysed; and wherein Seal further teaches using aluminum sulphate in the form of sodium alum to precipitate the C. diphtheria protein. Therefore, the Examiner reasonably interprets the aluminum-containing salts taught as aluminum sulphate by Chatel and sodium alum as taught by Seal will bind to protein within the microbial broth and not to the bacterial capsular polysaccharides of S. pneumoniae taught by Han in view of the disclosure of Wu as discussed above.
Thus, one of ordinary skill in the art would have been motivated and would have had a reasonable expectation of success to use the teachings of Chatel and Seal within the purification method of Han in order to conjugate the isolated and purified serotype 15B polysaccharide of Han to the carrier protein exemplified as CRM197 of Han; as Chatel teaches aluminum sulphate is a known flocculating agent after bacterial cells are lysed within a microbial broth and as evidenced by Wu, the aluminum adjuvant (alum) does not bind to unconjugated polysaccharides of S. pneumoniae as discussed in greater detail within the 103 rejection below.
With respect to Applicant’s argument (F), the Examiner respectfully notes MPEP 804(I)(B)(1) states a complete response to a nonstatutory double patenting (NSDP) rejection is either a rely by Applicant showing the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer with a reply to the Office action.
The Examiner respectfully notes the preceding explanation above addresses Applicant’s argument that the claims subject to the rejection are patentably distinct from the reference claims as discussed above; and that within the response to the previous Office action Applicant did not file a terminal disclaimer against U.S. Appl’ 17/799,992.
Moreover, with particular respect to Applicant’s argument the instant claims were filed earlier than the asserted reference claims and thus the instant claims cannot be invalidated for ODP by any of the later filed claims co-pending in U.S. Patent Application No. 17/799,992.
The Examiner also respectfully notes MPEP 804(I)(B)(1)(b)(i) states if a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the Examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent. However, since the 103 rejection has been maintained as discussed above and a new 112(b) rejection is made as discussed below, the ODP rejection in view of U.S. Appl’ 17/799,992 is not the only rejection remaining within this Office Action.
Thus, Applicant’s arguments (A)-(F) have been fully considered but are not found persuasive.
Claim Objections
Claims 1, 33 and 43 are objected to because of the following informalities:
(i) Claim 1, line 3, recites “a solution comprising a bacterial capsular polysaccharide and one or more contaminants”. The Examiner respectfully notes this is the second recitation of this limitation as this limitation is already recited in claim 1, lines 1-2. Therefore, to promote clarity the Examiner suggests replacing the phrase “a solution” with “the solution” and “a bacterial capsular polysaccharide” with “said bacterial capsular polysaccharide” as discussed above.
(ii) Claim 1, line 4, recites “in sufficient concentration” when referring to the amount of flocculating agent added to the solution, however this phrase is clearly missing the article “a” immediately before word “sufficient” as this is the first recitation of this limitation. Therefore, to promote clarity the Examiner suggests inserting the word “a” immediately before the word “sufficient” as discussed above.
(iii) Claim 33, recites “the final concentration of alum in the solution ranges from 1% to 5%”, which is referencing a weight percent of alum within the solution of claim 1.
Therefore, to promote clarity the Examiner suggests inserting the phrase “(w/v)” immediately after the phrase “5%”.
(iv) Claim 43, last line of the claim, recites “34,35B” which is clearly missing a blank space between the comma and the phrase “35B”. Thus, to promote clarity the Examiner suggests inserting said blank space as discussed above.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-5 and 28-43 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.
Claim 1, last line of the claim, recites “alum” as the flocculating agent. Claim 4 recites said alum may comprise one of the listed salts recited within claim 4.
However, the Examiner respectfully notes the specification does not explicitly define the term “alum”.
The Examiner respectfully notes the specification only exemplifies “alum” as;
(i) containing potassium, sodium or ammonium ions, see pg. 11, lines 30-35;
(ii) may be aluminum phosphate, aluminum sulfate or aluminum hydroxide, see pg. 78, lines 10-15 see pg. 78, lines 10-15; or
(iii) aluminum salts per se, see pg. 78, lines 15-20.
Additionally, the Examiner respectfully notes nowhere within the specification does Applicant suggest what “alum” is not or does not contain. Therefore, based on the absence of a definition of “alum” and the lack of any suggestion, advice or guidance within the specification as to what structures are not to be included within the term “alum”, the Examiner cannot determine the metes and bounds of the term “alum” as it relates to the flocculating agent used within the method of claim 1.
Furthermore, as disclosed by Thakkar et al. (Published 08 October 2016, “Methods to Prepare Aluminum Salt-Adjuvanted Vaccine” in Fox, C. B. (ed.), Vaccine Adjuvants: Methods and Protocols, Methods in Molecular Biology (New York, Springer Science+Business Media, 2017), Vol. 1494, pp. 181-199, PTO-892), Thakkar discloses aluminum salt-containing adjuvants are often referred to as “alum” in the literature. However, chemically, alum is potassium aluminum sulfate (KAl(SO4)2·12H2O), see pp. 182, introduction, paragraph 2 – pg. 183, paragraph 1.
Thus, the term “alum” is unclear and indefinite as to what structures are to be included and more importantly excluded within the term “alum” with respect to claim 1 and claim 4.
Claims 3, 5 and 28-43 are included in this rejection as they depend from or rely on the method of claim 1.
In the interest of compact prosecution, the Examiner will interpret the word “alum” in view of the exemplifications of “alum” within Applicant’s disclosure and discussed above to mean aluminum-containing salt.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, 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.
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.
Claims 1, 3-5 and 28-43 are rejected under 35 U.S.C. 103 as being unpatentable over Han et al. (Published 10 November 2016, US-20160324949-A1, PTO-892 mailed 05/21/2024) in view of Seal et al. (Published Sep.-Oct. 1941, The Journal of Infectious Diseases, Vol. 69, No 2, pp. 102-107, PTO-892 mailed 03/11/2025) and Chatel (Published 24 December 2015, US-20150368292-A1, PTO mailed 05/21/2024) as evidenced by Wu et al. (Published 11 September 2025, Analytical Chemistry, Vol. 97, Issue 37, pp. 20361-20371, PTO-892).
Han teaches isolated Streptococcus pneumoniae serotype 15B capsular polysaccharide (e.g. the bacterial capsular polysaccharide, required in claim 1, line 1) and processes for their preparation, see abstract; wherein the process comprising the steps of, see paragraph [0011]; (a) preparing a fermentation culture of Streptococcus pneumoniae serotype 15B bacterial cells, see paragraph [0012], the fermentation was a broth (e.g. a solution, required in claim 1, line 3), inactivated by the addition of N-lauroyl sarcosine and purified by ultrafiltration and diafiltration, see paragraph [0249]; (b) lysing the bacterial cells in said fermentation culture (e.g. the bacterial capsular polysaccharide and one or more contaminants, required in claim 1, line 3), see paragraph [0013]; (c) purifying Streptococcus pneumoniae serotype 15B capsular polysaccharide from the fermentation culture, see paragraph [0014]; and (d) sizing the purified Streptococcus pneumoniae serotype 15B capsular polysaccharide by high pressure homogenization, see paragraph [0015].
Han teaches the temperature of step (c) purifying Streptococcus pneumoniae serotype 15B capsular polysaccharide is maintained between 15°C and 45°C, where 45°C is within the range required in claims 34-35, see paragraph [0115].
Han teaches the duration of step (c) is between 0.1 hr (i.e. 6 min) to 10 hrs, see paragraph [0114].
Han teaches the serotype 15B polysaccharide may then be isolated from the cell lysate using purification techniques known in the art, including the use of centrifugation, depth filtration, precipitation, ultra-filtration, treatment with activate carbon (e.g. performing carbon filtration required in claim 40), diafiltration and/or column chromatography, see paragraph [0046].
Han teaches immunogenic conjugates comprising Streptococcus pneumoniae serotype 15B capsular polysaccharide covalently linked to a carrier protein for their preparation in immunogenic compositions and vaccines, see paragraph [0001]. Han preferably teaches the carrier protein is non-toxic and non-reactogenic, see paragraph [0128]; Han teaches the carrier protein is CRM197, see paragraph [0008]; and wherein CRM197 is a nontoxic but antigenically identical variant of diphtheria toxin, see paragraph [0129].
Although, Han does not expressly disclose using a flocculating agent (present claims 1, 3, 4, 5, 28-29, 33 and 36). Han also does not expressly disclose adjusting the pH to 5 or less (present claims 30-33); or the specific sequence of filtration steps required in claims 38-41.
However, in the same field of endeavor of purifying microbial harvests for preparing bacteria-based vaccines, Seal teaches studies on the purification of alum-precipitated diphtheria toxoid (e.g. contaminants comprise bacterial cell proteins, required in claim 1, line 6), see pg. 102, title. Seal teaches precipitation with sodium alum, wherein the sodium salt (Na2SO4, Al2(SO4)3, 24H2O) was used instead of the usual potassium salt, see pg. 102, right column, paragraph 2, lines 1-3.
Seal teaches the required volume of alum was added in the form of a 10% solution to the untreated or the treated toxoids and the mixtures allowed to stand in the incubator at 37°C for one-half to 1 hour and overnight in the cold room, see pg. 102, right column, paragraph 2, lines 1-3.
Seal teaches different concentrations of alum and at various pH values, for example, Seal teaches an alum concentration at 2% and a pH 4.0, see pg. 103, Table 1, last row of the table.
Seal teaches the precipitates were centrifuged down, washed twice with physiological salt solution and then resuspended in the same solution or in 0.5% sodium phosphate (Na2HPO4, 12 H2O) solution equal to the original volume of the toxoid (e.g. Seal demonstrates the flocculated material containing the bacterial cell protein is separated from the liquid, required in claim 1), see pg. 102, right column, Precipitation with sodium alum, paragraph 1.
Seal teaches as would be expected, all of the alum-precipitated toxoids were more antigenic than the crude toxoid from which they were made, see pg. 105, right column, Antitoxin production, paragraph 2.
The concentration of the flocculating agent, the pH of the solution, and the duration of flocculation were all taught by Seal as discussed above and lie within the ranges of present claims 5, 28-33 and 36, respectively. It would have been prima facie obvious before the invention’s effective filing date to have added a flocculating agent as taught by Seal above because the sodium alum taught by Seal successfully separated bacterial cell protein for preparing more antigenic bacteria-based immunogenic compositions or vaccines.
Additionally, Chatel teaches a method of clarifying a microbial harvest by adding an amount of a flocculant, see abstract.
Chatel teaches clarification is the process to remove solid particulates, where clarification can lower the burden on subsequent chromatographic steps during purification. Typical clarification steps include a centrifugation step, see paragraph, [0116].
Chatel exemplifies the clarification method, see pg. 7, left column, item 4, which comprises, (a) harvesting a microbial cell broth, see paragraph [0130]; (b) adding an amount of a flocculant to achieve a particle size distribution by volume of about 5% or less particles in the size range of 5 µm or less, see paragraph [0131]; and (c) clarifying the flocculated harvest, see paragraph [0132].
Chatel teaches within the method of any of the preceding items the method further comprises an additional step between step (a) and (b); where (b’) teaches pre-treating the harvest by (i) mechanical or chemical lysis, see paragraph [0133].
Chatel exemplifies flocculants include chemical flocculants such as aluminum sulphate, see paragraph [0104].
Therefore, with respect to the limitation “to produce flocculated material comprising said contaminants and liquid comprising said bacterial capsular polysaccharide” as required in claim 1, lines 4-5; the Examiner reasonably interprets this limitation as a physical consequence of introducing the alum within the liquid comprising the contaminants and bacterial polysaccharide.
Additionally, in claim 1, line 6, Applicant recites said contaminants comprise bacterial cell proteins, therefore the Examiner reasonably interprets the alum introduced within claim 1 binds to the bacterial cell proteins and does not bind to the bacterial capsular polysaccharides.
Furthermore, since the combination of Han, Seal and Chatel each teach purifying microbial harvests from lysed bacterial cells, and wherein Seal teaches the use of sodium alum in precipitating the C. diphtheria protein; and Chatel specifically teaches the use of a flocculating agent, such as aluminum sulphate, after the cells are lysed in clarifying the microbial broth; the Examiner reasonably interprets the physical consequence as recited in claim 1, lines 4-5 are met by the combined teachings of Han, Seal and Chatel as discussed above.
Additionally, as evidenced by Wu, Wu discloses multivalent pneumococcal conjugate vaccine (PVC) antigens are bound to the aluminum adjuvant (alum) in the vaccine through CRM197-alum interactions, where unconjugated polysaccharide species are not bound to the aluminum adjuvant. See pg. 20361, right column, paragraph 2.
Therefore, one of ordinary skill in the art would have been motivated to purify S. pneumoniae serotype 15B capsular polysaccharide from the fermentation culture, by specifically removing the bacterial cell proteins of S. pneumoniae before conjugation to CRM197 as the carrier protein as taught by Han above in order to minimize impurities and therefore adverse side effects of administering a S. pneumoniae vaccine containing bacterial cell proteins of S. pneumoniae or the possibility that any amount of S. pneumoniae polysaccharides conjugate to S. pneumoniae bacterial proteins as Han explicitly prefers carrier proteins be non-toxic and non-reactogenic.
One of ordinary skill in the art would have had a reasonable expectation of success of adding the flocculating agent of Seal into the method of Han as discussed above; as Chatel teaches the use of aluminum sulphate in microbial cell cultures as a flocculant after the microbial broth of Chatel is mechanically or chemically lysed therefore releasing unconjugated bacterial polysaccharides into the broth as a known consideration in the art; and as evidenced by Wu, unconjugated capsular polysaccharide species of S. pneumoniae do not bind to alum, rather these polysaccharides bind when conjugated to a protein exemplified as CRM197 by Wu as discussed above.
With respect to the sequence of purification steps recited in present claims 38-41, it would have been within the scope of the artisan through routine experimentation and optimization to separate the flocculated material taught by the combination of Han and Seal and arrive at the claimed invention required in claims 38-41 as Han already teaches the purification methods of centrifugation, depth filtration, ultra-filtration, diafiltration and treatment with activated carbon in purifying the Streptococcus pneumoniae serotype 15B polysaccharide as discussed above. See MPEP 2144.04(IV)(C) which recites “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results”.
Additionally, one of ordinary skill in the art would have had a reasonable expectation of success to incorporate the purification steps of present claims 38-41 into the method of Han, as Han is drawn to using centrifugation, depth filtration, ultra-filtration, diafiltration and treatment with activated carbon in purifying the Streptococcus pneumoniae serotype 15B polysaccharide as discussed above.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated the sodium alum taught by Seal as a flocculating agent in the purification step (c) as taught by Han above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to purify the Streptococcus pneumoniae serotype 15B capsular polysaccharide from the lysed fermentation culture to minimize the impurities and therefore adverse effects of administering a S. pneumoniae immunogenic composition or vaccine taught by Han by specifically removing the bacterial cell proteins of Streptococcus pneumoniae within the lysed culture broth of Han; therefore isolating the serotype 15B polysaccharides using purification techniques known in the art, including the use of centrifugation as taught by Han above; and thus further allowing the purified capsular polysaccharides of Streptococcus pneumoniae to be conjugated to the non-toxic and non-reactogenic carrier protein exemplified as CRM197 of Han as discussed above.
One of ordinary skill in the art would have had a reasonable expectation of success to have included the flocculating agent of sodium alum as taught by Seal into the purification process of Han, as Chatel teaches the use of aluminum sulphate as a flocculating agent after the cells are lysed in clarifying a microbial broth; and as evidenced by Wu unconjugated polysaccharide species of S. pneumoniae are not bound to the aluminum adjuvant (alum) as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
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 1, 3-5 and 28-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4-6 of copending Application No. 17/799,992 (amended claim set filed 08/19/2025, Applicant: Pfizer Inc.) in view of Han et al. (Published 10 November 2016, US 20160324949 A1, PTO-892 mailed 05/21/2024) and Seal et al. (Published Sep.-Oct. 1941, The Journal of Infectious Diseases, Vol. 69, No 2, pp. 102-107, PTO-892 mailed 03/11/2025) as evidenced by Wu et al. (Published 11 September 2025, Analytical Chemistry, Vol. 97, Issue 37, pp. 20361-20371, PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to a method of purifying a bacterial polysaccharide.
Reference claim 1 recites a method for purifying a saccharide derived from bacteria from a solution comprising said saccharide and contaminants following fermentation, wherein said method comprises the following steps: a) acid hydrolysis; b) flocculation; c) a first ultrafiltration/diafiltration (UFDF-1); d) carbon filtration; e) chromatography; and f) a second ultrafiltration/diafiltration (UFDF-2).
Reference claims 4-6 recite wherein the bacteria is any one of and including Streptoccoccus pneumoniae.
Reference claim 14 recites wherein the flocculation of step (b) comprises the use of aluminum.
Although, ‘992 does not recite wherein the flocculating agent is alum (present instant claims 1, 3, 4, 5, 28-29, 33 and 36). ‘992 also does not expressly recite adjusting the pH to 5 or less (present instant claims 30-33); the specific sequence of filtration steps required in present instant claims 38-41; or the serotype of the Streptococcus pneumoniae bacteria required in present instant claim 43.
However, in the same field of endeavor of purifying microbial harvests for preparing bacteria-based vaccines, Han teaches isolated Streptococcus pneumoniae serotype 15B capsular polysaccharide and processes for their preparation, see abstract; wherein the process comprising the steps of, see paragraph [0011]; (a) preparing a fermentation culture of Streptococcus pneumoniae serotype 15B bacterial cells, see paragraph [0012], the fermentation was a broth, inactivated by the addition of N-lauroyl sarcosine and purified by ultrafiltration and diafiltration, see paragraph [0249]; (b) lysing the bacterial cells in said fermentation culture (e.g. contaminants, required in instant claim 1, line 2), see paragraph [0013]; (c) purifying Streptococcus pneumoniae serotype 15B capsular polysaccharide from the fermentation culture, see paragraph [0014]; and (d) sizing the purified Streptococcus pneumoniae serotype 15B capsular polysaccharide by high pressure homogenization, see paragraph [0015].
Han teaches the temperature of step (c) purifying Streptococcus pneumoniae serotype 15B capsular polysaccharide is maintained between 15°C and 45°C, where 45°C is within the range required in instant claims 34-35, see paragraph [0115].
Han teaches the duration of step (c) is between 0.1 hr (i.e. 6 min) to 10 hrs, see paragraph [0114].
Han teaches the serotype 15B polysaccharide may then be isolated from the cell lysate using purification techniques known in the art, including the use of centrifugation, depth filtration, precipitation, ultra-filtration, treatment with activate carbon (e.g. performing carbon filtration required in instant claim 40), diafiltration and/or column chromatography, see paragraph [0046].
Han teaches immunogenic conjugates comprising Streptococcus pneumoniae serotype 15B capsular polysaccharide covalently linked to a carrier protein for their preparation in immunogenic compositions and vaccines, see paragraph [0001].
In addition, Seal teaches studies on the purification of alum-precipitated diphtheria toxoid (e.g. bacterial cell proteins, required in instant claim 1), see pg. 102, title. Seal teaches precipitation with sodium alum, wherein the sodium salt (Na2SO4, Al2(SO4)3, 24H2O) was used instead of the usual potassium salt, see pg. 102, right column, paragraph 2, lines 1-3.
Seal teaches the required volume of alum was added in the form of a 10% solution to the untreated or the treated toxoids and the mixtures allowed to stand in the incubator at 37°C for one-half to 1 hour and overnight in the cold room, see pg. 102, right column, paragraph 2, lines 1-3
Seal teaches different concentrations of alum and at various pH values, for example, Seal teaches an alum concentration at 2% and a pH 4.0, see pg. 103, Table 1, last row of the table.
Seal teaches the precipitates were centrifuged down, washed twice with physiological salt solution and then resuspended in the same solution or in 0.5% sodium phosphate (Na2HPO4, 12 H2O) solution equal to the original volume of the toxoid (e.g. Seal demonstrates the flocculated material containing the bacterial cell protein is separated from the liquid, required in instant claim 1), see pg. 102, right column, Precipitation with sodium alum, paragraph 1.
The concentration of the flocculating agent, the pH of the solution, and the duration of flocculation were all taught by Seal as discussed above and lie within the ranges of present instant claims 5, 28-33 and 36. It would have been prima facie obvious before the invention’s effective filing date to have added a flocculating agent as taught by Seal because the sodium alum taught by Seal successfully separated bacterial cell proteins for preparing more antigenic bacteria-based immunogenic compositions or vaccines.
Additionally, as evidenced by Wu, Wu discloses multivalent pneumococcal conjugate vaccine (PVC) antigens are bound to the aluminum adjuvant (alum) in the vaccine through CRM197-alum interactions. Unconjugated polysaccharide species are not bound to the aluminum adjuvant. See pg. 20361, right column, paragraph 2.
Therefore, one of ordinary skill in the art would have been motivated to purify S. pneumoniae serotype 15B capsular polysaccharide from the fermentation culture of ‘992, by specifically removing the bacterial cell proteins of S. pneumoniae before potential conjugation to CRM197 as a carrier protein as taught by Han above in order to minimize impurities and therefore adverse side effects of administering a S. pneumoniae vaccine containing bacterial cell proteins of S. pneumoniae or the possibility that any amount of S. pneumoniae polysaccharides conjugate to S. pneumoniae bacterial proteins as Han explicitly prefers carrier proteins be non-toxic and non-reactogenic.
One of ordinary skill in the art would have had a reasonable expectation of success of adding the flocculating agent of Seal into the method of ‘992 as discussed above; as ‘992 recites the use of aluminum as a flocculating agent within the flocculation step in microbial cell broth after said microbial broth of ‘992 is chemically lysed, specifically by acid hydrolysis as recited by ‘992 in reference claim 1; and as evidenced by Wu which discloses unconjugated capsular polysaccharide species of S. pneumoniae do not bind to alum rather these polysaccharides bind when conjugated to a carrier protein exemplified as CRM197 by Wu as discussed above.
With respect to the sequence of purification steps recited in present instant claims 38-41, it would have been within the scope of the artisan through routine experimentation and optimization to separate the flocculated material recited and/or taught by the combination of ‘992, Han and Seal respectively and arrive at the claimed invention required in instant claims 38-41 as Han already teaches the purification methods of centrifugation, depth filtration, ultra-filtration, diafiltration and treatment with activated carbon in purifying the Streptococcus pneumoniae serotype 15B polysaccharide as discussed above. See MPEP 2144.04(IV)(C) which recites “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results”.
One of ordinary skill in the art would have had a reasonable expectation of success to incorporate the purification steps of present instant claims 38-41 into the method of ‘992, as ‘992 is already drawn to using ultra-filtration, diafiltration and carbon filtration in purifying Streptococcus pneumoniae bacterial saccharides.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated the sodium alum taught by Seal as a flocculating agent into the method as recited by ‘992 above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to purify a Streptococcus pneumoniae saccharide as recited by ‘992 above for conjugation with a carrier protein in a bacterial vaccine as taught by Han above.
One of ordinary skill in the art would have had a reasonable expectation of success to have incorporated the sodium alum taught by Seal into the method as recited by ‘992 above; as ’992, Han and Seal are all drawn to purifying microbial harvests; Han teaches purifying S. pneumoniae serotype 15B capsular polysaccharides for immunogenic compositions and vaccines; Wu discloses alum does not bind to unconjugated polysaccharide species of S. pneumoniae; and ‘992 explicitly recites the use of aluminum within the flocculation step as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined recitations of ‘992 and the teachings of the prior art.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed in this action.
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/JARET J CREWS/Examiner, Art Unit 1691
/SAVITHA M RAO/Primary Examiner, Art Unit 1691