DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/14/2025 has been entered.
3. Applicants’ response and amendment of 11/14/2025 are acknowledged. Claims 1 and 27 have been amended. Claim 35 has been canceled.
Status of Claims
4. Claims 1-13, 27-31 and 34 are pending in this application. Claims 1 and 27 have been amended. Claim 35 has been canceled. By applicant’s amendment of 4/8/2022 claims 14-26 and 32-33 have been canceled.
Claim Rejections - 35 USC § 103 Maintained
5. Rejection of claims 1-12, 27-28 and 34 under 35 USC § 103 a being obvious over Verlant Vincent (US 20140105927 published April 2014; published March 2013, in view of Biemans et al. (WO 2004081515) and Pauksens et al. (Clinical and Vaccine Immunology, vol. 21, no. 5, March 2015( Art of record 1449), as evidenced by Clapp et al. (JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 2, FEBRUARY 2011), is maintained.
Note: amended claim 1 recites product by process. MPEP 2113 recites: 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)
The claims are drawn to:
Amended claim 1. An immunogenic composition comprising detoxified pneumolysin adsorbed onto aluminium phosphate, wherein more than 85% of the detoxified pneumolysin is adsorbed onto aluminum phosphate, wherein the immunogenic composition is prepared by a process for adsorption of detoxified pneumolysin onto aluminium phosphate comprising admixing detoxified pneumolysin and the aluminium phosphate (dPly:Al3+) at a ratio of I:3 and at a pH range between 5.5 to 6.1.
Claim 9. An immunogenic composition according to claim 8, wherein the detoxified pneumolysin is conjugated to a saccharide, wherein the saccharide is a capsular saccharide of S. pneumoniae.
Claim 10. An immunogenic composition according to claim 1, further comprising PhtD adsorbed onto aluminum phosphate.
Verlant Vincent US 20140105927 teaches an immunogenic composition and a vaccine comprising unconjugated chemically detoxified pneumolysin, unconjugated Poly Histidine family protein D (PhtD) and 10 distinct pneumococcal polysaccharides, all adsorbed on aluminum phosphate (para 0011 -0026, 0078-0098, 0127-0135, examples 1 -6) in a method to enhance antibody-mediated opsonic activity against a Streptococcus pneumoniae serotype. The art teaches in Example 1 producing vaccines by admixing 10/30 µg of dPly adjuvanted with Aluminum phosphate, 10/30 µg of dPly and 10/30 µg of PhtD adjuvanted with Aluminum phosphate (Para 0179). Further, the art teaches antigens adjuvanted to Aluminum phosphate, said antigens are S. pneumoniae capsular saccharides serotypes ((Para 0179).
As to amended limitations in claim 1 ( adsorption of Dply to aluminium phosphate, ratios and pH) Verlant Vincent teaches those limitations. See para 0133, 0159, 0179, 0180, 0181, 0196, 0210, 0223, 0224, 0225,0290, 0294, 0311.
Verlant Vincent para [0290] recites: The 1 0V vaccine contains S. pneumoniae capsular saccharide serotype 1, 4, 5, 6B, 7F, 9\7, 14, 18C, 19F and 23F conjugates adsorbed onto aluminium phosphate together at a human dose of 1, 3, 1, 1, 1, 1, 1, 3, 3, 1 μg (the saccharides were individually adsorbed to aluminium phosphate, they were then mixed together and the level of aluminium phosphate adjusted to 500 μg).
Verlant Vincent teaches vaccine and pharmaceutically acceptable carrier or excipient (see par 0160-0161). Verlant Vincent at [0087] teaches pneumolysin is administered after being detoxified (i.e. rendered non-toxic to a human when provided at a dosage suitable for protection). As used herein, it is understood that the term "dPly" refers to detoxified pneumolysin suitable for medical use (i.e., nontoxic). Pneumolysin may be detoxified chemically and/or genetically. pneumococcal infections. Verlant Vincent teaches detoxified pneumolysin adsorbed onto aluminium phosphate (see para 0250, 0290, 0291). In the absence of evidence to the contrary the pH of said vaccine composition is comprised between 6 and 7, more than 85% of detoxified pneumolysin is adsorbed on aluminum phosphate and the detoxified pneumolysin adsorbed onto aluminum phosphate has a particle size less than 10micrometer. Verlant teaches limitations of claim 1-6, 10, 11, and 27-28 and 34.
Biemans et al. WO 2004 081515 A2 disclose vaccine compositions comprising unconjugated chemically detoxified pneumolysin and unconjugated Poly Histidine family protein D (PhtD) both adsorbed on aluminum phosphate. Biemans et al. teach pneumolysin is reduced by at least 90% following treatment with the cross-linking reagent to achieve detoxification of the pneumolysin. Methods of the invention lead to a reduction of the amount of toxicity and/or haemolytic activity of the toxin of at least 90%, preferably 95%, 96%, 98%, 99%, 99.5%, 99.9% or 99.99%. (Haemolytic activity is measured using the method of Example 3 and toxicity may be measured by the method of Example 5.) see page 14. Biemans et al. pH 6.5, 7 and 5-9 see pages 15,16. Biemans et al. teach alum adsorbed antigen and aluminum phosphate ( see pages 24, 25). In the absence of evidence to the contrary the pH of said vaccine composition is comprised between 6 and 7, more than 85% of detoxified pneumolysin is adsorbed on aluminum phosphate and the detoxified pneumolysin adsorbed onto aluminum phosphate has a particle size less than 10 micrometer, . see abstract, p. 11 line 23 - p. 18 line 31, p. 24 line 1 - p. 25 line 33, examples 6-8 and claims. Therefore, the art teaches subject-matter of claims 1-6, 8-11 and 27-28.
Similarly, Pauksens et al. also discloses vaccine compositions comprising unconjugated chemically detoxified pneumolysin and unconjugated Poly Histidine family protein D (PhtD) both adsorbed on aluminum phosphate in presence of further distinct pneumococcal polysaccharides conjugated to various distinct carrier proteins, e.g. protein D, Tetanus Toxoid, Diphtheria Toxoid, detoxified pneumolysin and PhtD, all adsorbed on aluminum phosphate for use in the prevention of pneumococcal infections (see abstract, p. 652 right-hand column first full paragraph, p. 653 first and second full paragraphs, p. 655 left-hand column line 1 - p. 657 left-hand column line 10 p. 658 right-hand column line 7 - p. 659 left-hand column third full paragraph and fig. 3-6). The disclosure of Pauksens et al. teach limitations of claims 1-5, 8-12 and 27-28.
Clapp et al. teach Adsorptive Capacity and Immunogenicity For vaccines ( see title). Clapp et al. teach for vaccines; the adsorptive capacity provides information regarding the maximum amount of a specific antigen that can be adsorbed onto the adjuvant under given conditions ( see page 389). Clapp et al. teach vaccines with adjuvants having a range of adsorption percentiles (3%–90% lysozyme adsorbed) were created using a commercial aluminum hydroxide adjuvant, phosphate-treated aluminum hydroxide adjuvant (10%, 85%, and 90%; note that the adjuvants with 85% and 90% antigen adsorption were vaccines of identical formulations prepared on different days), or a commercial aluminum phosphate adjuvant ( see page 389). It would have been obvious to one skilled in the art, at the time first inventor to combine the teachings of the references to obtain the instant invention. All the above references teach an immunogenic composition comprising detoxified pneumolysin adsorbed onto aluminum phosphate conjugated to capsular polysaccharide and PhtD. As determine the exact and optimal conditions required for said adsorption step using optimal buffers and pH etc. as it is well known in the art as Clapp et al. teach for vaccines, the adsorptive capacity provides information regarding the maximum amount of a specific antigen that can be adsorbed onto the adjuvant under given conditions ( see page 389).
Clapp et al. recites that “ Vaccines with adjuvants having a range of adsorption percentiles (3%–90% lysozyme adsorbed) were created using a commercial aluminum hydroxide adjuvant (3%), phosphate-treated aluminum hydroxide adjuvant (10%, 85%, and 90%; note that the adjuvants with 85% and 90% antigen adsorption were vaccines of identical formulations prepared on different days), or a commercial aluminum phosphate adjuvant (35%)”, see page 389. Clapp et al. further recites that “
aluminum phosphate adjuvant in saline with 80% or more of rPA adsorbed, and aluminum phosphate adjuvant in sodium phosphate buffer with no rPA adsorbed”, see page 391.
One would have had a reasonable expectation of success because methodologies have been taught by both prior arts. Therefore, the combination of the prior arts renders the instant claims prima- facie obvious absent evidence to the contrary. As to limitations such as % detoxified pneumolysin adsorbed to aluminum phosphate and its particle size, these would be considered optimization of experimental parameters and would be obvious to one of ordinary skill in the art. However, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235(CCPA 1955).
Therefore, it would have been prima facie obvious at the time of applicants’ invention to combine the composition and method of references to obtain the instant invention. It would have been obvious to one of ordinary skill in the art that to modify the percentages and a number of antigens and capsular polysaccharides in the immunogenic composition.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses, "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to combine known compositions, which function in a predictable manner to yield a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known compositions that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Note: Newly added claim 35 is also rejected under 103 as being obvious over the above references. The combined references teach the limitations of added claim 35. As to ratios and pH limits, those would be considered optimization of experimental parameters and would be obvious to one of ordinary skill in the art. However, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235(CCPA 1955).
Applicants’ Arguments
6. Applicant's arguments filed 11/14/2025 have been fully considered but they are not persuasive. Applicants Argue:
Solely in order to advance prosecution and without acquiescing to the appropriateness of the Office's rejection, claim 1 has been amended to incorporate the subject matter of claim 35, and claim 35 has been cancelled. Thus, claim 1 as amended recites:
An immunogenic composition comprising detoxified pneumolysin adsorbed onto aluminium phosphate, wherein more than 85% of the detoxified pneumolysin is adsorbed onto aluminium phosphate, wherein the immunogenic composition is prepared by a process for adsorption of detoxified pneumolysin onto aluminium phosphate comprising admixing detoxified pneumolysin and the aluminium phosphate (dPly:Al3+) at a ratio of 1:3 and at a pH range between 5.5 to 6.1.
Claim 1 has been amended to recite, inter alia, an immunogenic compos1t10n comprising detoxified pneumolysin absorbed onto aluminum phosphate, wherein the immunogenic composition is prepared by an admixing process with specific ranges - namely aluminium phosphate (dPly:Al3+) at a ratio of 1:3 and at a pH range between 5.5 to 6.1. For example, the specification at page 47 states that:
Using the process of Example 1 (pH5.5 to 6.1, ratio of dPly:Al3+ (from aluminium phosphate) of 1:3), completeness was improved of ~20% compared to other processes (pH5.5-6. l and ratio of dPly:Al3+ (from aluminium phosphate) of 1: l; pH5.5-6. l and ratio of dPly:Al3+ (from aluminium phosphate) of 1:2; pH6.5 and ratio of dPly:Al3+ (from aluminium phosphate) of 1:3) without addition of extra alum. A 96-99% completeness of adsorption was observed with the process of Example 1.
Accordingly, the claimed process which includes a pH range of 5.5 to 6.1 and a ratio of dPly:Al3+ (from aluminium phosphate) of 1:3 achieved a result that is 20% improved with respect to completeness of adsorption.
The claimed process unexpectedly improves the completeness of adsorption
The Specification establishes that the combination of the parameters: (i) a pH range of
5.5 to 6.1 and (ii) a ratio of dPly:Al3+ (from aluminium phosphate) of 1:3, achieved a result that is 20% improved as compared to other processes. Having only one of these parameters - a pH range of 5.5 to 6.1 or a ratio of dPly:Al3+ of 1:3 did not show a 20% improvement (see, Specification, page 47, Example 1). Accordingly, this combination shows an unexpected process improvement and is not obvious. The cited combination of references do not disclose, teach or suggest these features.
The O[fice has not established a prima facie case of obviousness
The USPTO bears the initial burden of establishing a prima facie case of obviousness.
MPEP § 2142. The MPEP is clear that: "[t]he key to supporting any rejection under 35 U.S.C. § 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious
... The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit." MPEP § 2143.
Applicant maintains that for the reasons of record submitted in the reply filed on May 9, 2025, the Office has not provided sufficient articulated reasoning to establish a prima facie case of obviousness:
Without providing any articulated reasoning, the Office asserts that in the absence of evidence to the contrary, three separate features are present, with a first feature being "more than 85% of the detoxified pneumolysin is adsorbed onto aluminum phosphate," the second feature being "the immunogenic composition has a pH between 6 and 7," and the third feature being "the detoxified pneumolysin absorbed onto aluminum phosphate has a particle size less than 10 micrometer." The Office asserts that these features are known but provides no evidence or reasoning to support this assertion. Instead, the Office appears to be relying on personal knowledge and/or unofficially taking Official Notice for a teaching of these features. (Reply, May 9, 2025, page 7).
In response, the Office states that "the arguments of patent attorneys cannot replace actual evidence in patent examination" and cites to (MPEP § 716.01 (c)(II). However, the Office has not fully addressed Applicant's remarks. According to MPEP § 2143, Office personnel are to continue to make appropriate findings of fact and must provide a reasoned explanation as to why the invention as claimed would have been obvious to a person of ordinary skill in the art at the relevant time (citing to In re Van Os, 844 F.3d 1359, 1361, 121 USPQ2d 1209, 1211 (Fed. Cir. 2017) ("Absent some articulated rationale, a finding that a combination of prior art would have been 'common sense' or 'intuitive' is no different than merely stating the combination 'would have been obvious."')). Thus, Applicant requested that the Office provide evidence as to why certain features relating to pH, particle size, and completeness of adsorption would have been obvious. The burden is on the Office to provide this evidence and obviousness rejections cannot be sustained by conclusory statements. MPEP 2143.
The Office also states that one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. In response, Applicant respectfully submits that it is appropriate to point out the deficiencies of individual references, particularly when those references do not recite the claimed elements. All of the claim limitations must be considered when assessing patentability. MPEP § 2143.03. If a claim limitation is not met by the prior art reference or other appropriate evidence, a rejection is inappropriate. The Office cannot ignore claim limitations.
In conclusion, the cited combination of references do not teach each of the recited features of claim 1. The Office cannot sustain obviousness rejections based on conclusory statements and claim limitations cannot be ignored. The recited process of claim 1 leads to unexpected improvements in the completeness of adsorption. None of the cited references, alone or in combination, disclose, teach, or suggest the recited combination of elements. Favorable reconsideration and withdrawal of the rejection of claim 1 is respectfully requested.
The dependent claims contain all of the features of the independent claim from which it depends. Favorable reconsideration and withdrawal of the rejection of the dependent claims is respectfully requested.
Office Response
8. Applicant's arguments filed 11/14/2025 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant’s argument about to amended limitations in claim 1 ( adsorption of dPly to aluminum phosphate, ratios and pH, Verlant Vincent teaches those limitations. See para 0133, 0159, 0179, 0180, 0181, 0196, 0210, 0223, 0224, 0225,0290, 0294, 0311. Verlant Vincent para [0290] recites: The 1 0V vaccine contains S. pneumoniae capsular saccharide serotype 1, 4, 5, 6B, 7F, 9\7, 14, 18C, 19F and 23F conjugates adsorbed onto aluminum phosphate together at a human dose of 1, 3, 1, 1, 1, 1, 1, 3, 3, 1 μg (the saccharides were individually adsorbed to aluminum phosphate, they were then mixed together and the level of aluminum phosphate adjusted to 500 μg).
Note : amended claim 1 recites product by process. MPEP 2113 recites: 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)
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, it would be prima facie obvious at the time the invention was made to combine the teachings of the references to obtain instant invention. One would have had a reasonable expectation of success because methodologies have been taught by both prior arts. Therefore, the combination of the prior arts renders the instant claims prima- facie obvious absent evidence to the contrary. As to limitations such as % detoxified pneumolysin adsorbed to aluminum phosphate and its particle size, these would be considered optimization of experimental parameters and would be obvious to one of ordinary skill in the art. However, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235(CCPA 1955).
Therefore, it would have been prima facie obvious at the time of applicants’ invention to combine the composition and method of references to obtain the instant invention. It would have been obvious to one of ordinary skill in the art that to modify the percentages and a number of antigens and capsular polysaccharides in the immunogenic composition.
In response to applicants’ arguments that “Office alleges that the combination of cited references disclose, teach, or suggest the features of claims 1-12, 27-28 and 34. However, instead of providing articulated reasoning for the claimed features: (i) more than 85% of detoxified pneumolysin is adsorbed on aluminum phosphate (see, claim 1), (ii) pH of said composition is comprised between 6 and 7 (see, claim 3), and (iii) the detoxified pneumolysin absorbed onto aluminum phosphate has a particle size less than 10 micrometer (see, claim 4), the Office takes the position that "in the absence of evidence to the contrary" these features are present. The Office has not established a prima facie case of obviousness.”
This is not find persuasive, applicants’ attention is directed to following:
This principle is clearly stated in MPEP 716.01(c) II:
The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965).
This means that while attorneys can present arguments and interpretations of evidence, their statements alone are not considered evidence.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses, "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to combine known compositions, which function in a predictable manner to yield a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known compositions that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Conclusion
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHATOL S SHAHNAN SHAH whose telephone number is (571)272-0863. The examiner can normally be reached on Mon-Tue, Thurs-Fri 12pm-8pm.
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/KHATOL S SHAHNAN SHAH/Examiner, Art Unit 1645
November 23, 2025
/JANA A HINES/Primary Examiner, Art Unit 1645