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 .
Claim Status
The amended claim set filed on 16 October 2025 is acknowledged. Claims 21-22, 24-25, 27-31, 34-35, and 37-44 are currently pending. Of those, claims 21-22, 24-25, 27-31, 34-35, and 37-40 are amended. Claims 41-44 are new, and no claims are withdrawn. Claims 1-20, 23, 26, 32-33, and 36 are cancelled. Claims 21-22, 24-25, 27-31, 34-35, and 37-44 will be examined on the merits herein.
Response to Amendment
The Applicants’ arguments filed 16 October 2025 are acknowledged. For clarity, in this action, said arguments will be referred to as “Remarks” and the Non-Final Office Action mailed 16 June 2025 will be referred to “NFOA”.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 16 October 2025 was filed after the mailing date of the NFOA on 16 June 2025. The submission is in compliance with the provisions of 37 CFR 1.97 in view of the appropriate fee submitted with the IDS. Accordingly, the information disclosure statement is being considered by the examiner.
No submission was received for Foreign Patent Document WO 2021/205017 A1. However, a copy of the document is attached with this action; thus, the reference is being considered.
Claim Interpretation
Claims 21-22 and 31 each recite, “the aluminum composition comprising: less than 1.25 ppb copper or a radical quenching compound which is L-methionine, in a molar concentration at least equivalent to the concentration of copper.” The broadest reasonable interpretation of this limitation is that the aluminum composition requires only one of either less than 1.25 ppb copper of L-methionine in a concentration at least equivalent to that of copper, not both.
Claims 21-22 and 31 each recite protein antigens or “immunogenic variants thereof”. The instant specification teaches, “Variants of a protein are typically characterized by possession of at least about 60%, for example at least about 70%, 75%, 80%,85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%or 99% sequence identity.” (pg. 16) Therefore, the broadest reasonable interpretation of the limitation encompasses immunogenic proteins with at least 60% sequence identity to the recited protein antigens.
Claims 24 and 34 each recite, “copper is in form of an ion, optionally as Cu+ or Cu2+.” MPEP 2111.04 states: “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure.” Thus, the “optional” limitation is interpreted as not limiting the scope of copper ion.
Rejection(s) Withdrawn
The objection to claims 28 and 35-36 is withdrawn in view of the amendments to the claims.
The rejection(s) of claims 23, 26, 32-33, and 36 under 35 U.S.C. 112(b), 112(a), 102(a)(1), and/or 103 are moot because the claims are cancelled.
The rejection(s) of claims 21-22, 24-25, 27-31, 34-35, and 37-40 under 35 U.S.C. 112(b) are withdrawn in view of the amendments to the claims.
The rejection of claims 21-22, 24-25, and 27-30 under 35 U.S.C. 112(a) is withdrawn in view of the amendments to the claims.
The rejection of claims 21-22, 25, and 27-29 under 35 U.S.C. 102(a)(1) is withdrawn in view of the amendments to the claims.
The provisional nonstatutory double patenting rejection over application 17/913,638 is withdrawn because the 17/913,638 application has been abandoned.
The provisional nonstatutory double patenting rejection over application 17/917,624 is withdrawn in view of the amendments to the claims.
The provisional nonstatutory double patenting rejection over application 17/393,888 is withdrawn in view of the amendments to the claims.
The nonstatutory double patenting rejections over US 11,110,170 B2, US 9,913,898 B2, US 9,895,437 B2, and US 9,895,437 B2 are withdrawn in view of the amendments to the claims.
Rejection(s) Maintained
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 103
Claims 21-22, 24-25, 27-28, 31, 34-35, and 37-38 remain rejected and claims 41 and 43 are newly rejected under 35 U.S.C. 103 as being unpatentable over Lundberg et al. (US 2016/0333056 A1; cited in IDS; here in “Lundberg”) as evidenced by Walpole et al. (2012, BMC Public Health) in view of Möhlen et al. (WO 2013/083726 A1; cited in IDS; herein “Möhlen”).
Regarding claims 21-22, 27, 31 and 37, Lundberg teaches a method comprising administering a pharmaceutical composition to a human (para. 198-199), wherein the pharmaceutical composition may comprise a polypeptide (i.e., a protein antigen), a L-methionine (i.e., a radical quenching compound) as a pharmaceutically acceptable excipient (para. 172-176 and 181), an aluminum adjuvant (para. 182), and polysorbate-20 as a stabilizing compound (i.e., a reactive compound) (para. 184). Lundberg teaches that polypeptide (i.e., protein antigen) of the composition may comprise Lip-S1D1-S2D1, Lip-S4D1-S3hybD1, and Lip-S5D1-S6D1, which have sequences given in SEQ ID NOs: 29, 27, and 33, respectively (para. 178 and 186), and are identical to instant SEQ ID NOs: 1-3, respectively (see alignments in Figures 1-3 below).
Regarding the limitation “a radical quenching compound which is L-methionine, in a molar concentration at least equivalent to the concentration of copper”, Lundberg teaches that the adjuvant used in the composition may be an aluminum adjuvant that makes a solution having less than 350 ppb heavy metal (e.g., copper); however, this concentration is not limited to a single metal, so it is assumed that the concentration of a single metal will be much lower than 350 ppb (para. 213). Lundberg’s preferred composition (para. 185) comprises 10 mM L-methionine (i.e., 0.01 mol/L), or 1.49 g/L (0.01mol/L *149.21 g/mol (molar mass of L-methionine) = 1.4921 g/L), which is greater than 350 ppb (i.e., 350 µg/L). Thus, the concentration of L-methionine in mol/L is greater than the concentration of copper in the composition.
Regarding the administration of OspA heterodimers, Lundberg teaches that the dosage for the vaccine may be between 0.02 µg and 3 µg antigen per kg body weight for adults and between 0.2 µg and 10 µg antigen per kg body weight for children (para. 220). For adults, this would result in a vaccine comprising between about 1.24 µg and 186 µg, based on the average adult weight of 62.0 kg (as evidenced by Walpole et al., Table 3). Lundberg also teaches that the dose may be administered from 1 to 3 times (para. 220).
Regarding claims 25 and 35, Lundberg teaches that the concentration of L-methionine may be 10 mM, i.e., 10 mmol/L (para. 185).
Regarding claims 28 and 38, Lundberg teaches that the Lip-S1D1-S2D1, Lip-S4D1-S3hybD1, and Lip-S5D1-S6D1 proteins are mixed at a molar ratio (i.e., weight ratio) of preferably 1:1:1 (para. 186).
Regarding claims 41 and 43, Lundberg teaches that the aluminum adjuvant may be aluminum hydroxide or aluminum phosphate (para. 182).
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Figure 1: Alignment of instant SEQ ID NO: 1 (Qy) with Lundberg’s SEQ ID NO: 29 (Db), both identified as Lip-S1D1-S2D1.
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Figure 2: Alignment of instant SEQ ID NO: 2 (Qy) with Lundberg’s SEQ ID NO: 27 (Db), both identified as Lip-S4D1-S3hybD1.
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Figure 3: Alignment of instant SEQ ID NO: 3 (Qy) and Lundberg’s SEQ ID NO: 33 (Db), both identified as Lip-S5D1-S6D1.
However, Lundberg does not teach a composition comprising less than 1.25 ppb copper, as in claims 21-22 and 31, including copper in the form of an ion, as in claims 24 and 34, or a vaccine having the dosages recited in claims 21-22 and 31.
Regarding claims 21-22 and 31, Möhlen teaches that a protein composition (such as a vaccine comprising a protein antigen) preferably has less than 1 or 0.2 ppb copper, because the presence of copper affects the storage stability of the compositions (pg. 27, lines 19-30). Möhlen also teaches that the presence of heavy metals (including copper) in aluminum-adjuvanted compositions affects the shelf life of proteins containing proteins and that the degradation of proteins increases as time passes; therefore, reduced presence of heavy metals improves protein stability and shelf life (pg. 20, lines 9-27).
Regarding claims 24 and 34, Möhlen teaches that copper may be in the form of an ion (pg. 52, line 15, and pg. 70, line 8 – pg. 72, line 12).
Regarding claims 27 and 37, Möhlen teaches that the protein composition may further comprise a reactive compound, including a redox active compound, radical building compound, and/or a stabilizing compound (pg. 29, line 24 – pg. 30, line 9).
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to modify the vaccine containing OspA protein antigens, an aluminum adjuvant, and the radical-quenching compound L-methionine taught by Lundberg by using an aluminum adjuvant composition that results in a vaccine comprising less than 1 ppb copper, as taught by Möhlen, and further modify the composition by optimizing the dosage for administration to adults or children based on the parameters taught by Lundberg, thereby arriving at the claimed invention. The person of ordinary skill in the art would have been motivated to make the modification because Möhlen teaches that the presence of copper causes protein degradation, which affects the stability of the proteins in the composition and negatively impacts the shelf life and efficacy of the composition. Regarding the dosage of the composition to be administered, one would be motivated to use the parameters set forth by Lundberg to optimize the dosage of the vaccine based on the target population. Therefore, the combination is also desirable (see MPEP 2144(II)). The person of ordinary skill in the art would have had a reasonable expectation of success because Möhlen demonstrates that compositions containing less than 1.25 ppb copper show less protein degradation compared to those with higher copper and heavy metal concentrations. Therefore, the combination leads to expected results because each element performs the same function as is does individually.
Regarding the limitation, “an aluminum composition with increased antigen bioavailability”, where the claimed and prior art products are identical or substantially identical in structure or composition, … 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). Because the combination of Lundberg and Möhlen results in a method comprising administering a composition substantially identical to the aluminum composition of the instant claims (i.e., a composition comprising less than 1.25 ppb copper or L-methionine in a molar concentration at least equivalent to the concentration of copper, an aluminum adjuvant, at least one of the recited reactive compounds, and one of the recited protein antigens), the property of “increased antigen bioavailability” is presumed to be inherent to the combination product. "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).
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, 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 that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, all elements (i.e., aluminum composition comprising less than 1.25 ppb copper, aluminum composition comprising L-methionine, Borrelia OspA heterodimer vaccine and dosages) were known in the art. In addition, combining these elements yields a method/composition wherein each element merely performs the same function as it does separately; thus, the results of the combination would be recognized as predictable to one of ordinary skill in the art. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Regarding the dosages of the OspA heterodimer proteins of claims 29 and 39-40, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985)) (see MPEP 2144.05.01). The courts have also found that “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). See MPEP 2144.05(II). Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Response to Arguments
Applicant argues (Remarks, pg. 18-19) that improved antigen bioavailability was an unexpected result of reducing copper levels below 1.25 ppb or using at least an equimolar amount of L-methionine and that the bioavailability achieved using less than 1.25 ppb copper or claimed concentration of L-methionine is a difference in kind.
This argument has been fully considered but is not persuasive. Regarding the argument of unexpected results, the data relied upon by Applicant in FIGs, 1A-B and Table 4 does not show that the differences between Alum lots A and B or between the “w/o Additives” and “w/ L-Methionine” groups are statistically significant. MPEP 716.02(b)(I) states: “The evidence relied upon should establish ‘that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.’ Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992)” Furthermore, the antigen recovery in the Alum Lot B (i.e., low copper) w/o additives groups and the Alum Lot A (i.e., high copper) with L-methionine groups are very similar, indicating that the change in antigen recovery does not demonstrate “a marked improvement, over the results achieved under other ratios, as to be classified as a difference in kind, rather than one of degree.” (In re Waymouth, 499 F.2d 1273, 1276, 182 USPQ 290, 293 (CCPA 1974)). See MPEP 716.02.
Applicant argues (Remarks, pg. 16-17 and 19) that Lundberg does not teach an aluminum composition comprising less than 1.25 ppb copper or L-methionine in at least an equimolar amount to copper because para. 213 of Lundberg, which teaches adjuvants having less than 350 ppb heavy metal, but not L-methionine, and para. 185 of Lundberg, which teaches the concentration of L-methionine, but does not mention copper. Because Lundberg does not teach these elements, Applicant argues, Lundberg and Möhlen do not provide a reason to have reduced copper levels below 1.25 ppb or use at least an equimolar amount of -L-methionine to improve antigen availability.
Applicant also argues (Remarks, pg. 20) that the combination of Lundberg and Möhlen set forth in the NFOA would have impermissibly altered the technical principles underlying the portion of Möhlen cited in the NFOA.
These arguments have been fully considered but are not persuasive. In response to the argument that Lundberg does not teach an aluminum composition comprising less than 1.25 ppb copper or L-methionine in at least an equimolar amount to copper, one cannot show nonobviousness 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). Furthermore, as was set forth in the 103 rejection of the NFOA and in the 103 rejection above, Lundberg does teach L-methionine in a concentration greater than the total concentration of heavy metal in the composition, which is greater than the concentration of copper in the composition (see para. 20 above). While Lundberg does not specifically teach that L-methionine is included in a molar concentration at least equivalent to the concentration of copper, the 10 mM concentration of L-methionine in the composition taught in para. 185 is a higher than the 350 ppb total heavy metal concentration taught in para. 213; thus, 10 mM L-methionine must be greater than the concentration of copper in an adjuvanted composition comprising less than 350 ppb heavy metals. Applicant has not pointed to any errors in the calculations to determine the amount of L-methionine relative to the concentration of heavy metals anywhere in the Remarks. In response to applicant's argument that neither Lundberg nor Möhlen provide a motivation to improve antigen availability, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). “It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006)” (see MPEP 2144(IV)) “‘[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.’ Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
In response to the argument that the combination set forth in the NFOA would have altered the technical principles underlying Möhlen, it is not clear from the arguments what technical principles Applicant is referring to or, if referring to Möhlen’s teachings regarding storage stability and shelf life, how the combination alters those principles.
Applicant argues (Remarks, pg. 20-21) that there was no reasonable expectation of improving antigen bioavailability using less than 1.25 ppb copper or L-methionine in at least an equimolar amount to copper.
This argument has been fully considered but is not persuasive. The combination set forth in the 103 rejection of the NFOA and in the 103 rejection above teaches a method comprising administering a composition substantially identical to that of amended claims 21-22 and 31. Thus the resulting effect of improved antigen bioavailability is presumed to be inherent to the composition because the modification has all structural features currently claimed. Where the claimed and prior art products are identical or substantially identical in structure or composition, … 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.
Double Patenting
Response to Arguments
For all double patenting rejections of record, applicant argues (Remarks, pg. 22) that none of the reference claims recite the specific combination of elements recited in the instant claims, and that Lundberg and Möhlen do not provide the motivation to use less than 1.25 ppb copper or L-methionine in a concentration at least equivalent to that of copper or predict that the copper or L-methionine concentrations would increase antigen bioavailability; nor do they provide the expectation of success necessary to arrive at the invention of the instant claims.
This argument has been fully considered but is not persuasive. Regarding the argument that Lundberg and Möhlen do not predict that the concentration of copper or L-methionine could result in increased antigen bioavailability, this argument has been addressed in para. 42 above. Regarding the argument that the reference claims in combination with Lundberg and Möhlen fails to provide the necessary motivation and expectation of success necessary to arrive at the instant claims, this argument is not persuasive because the following rejections have been amended to reflect the amendments to the instant claims.
The following rejections have been amended to reflect the amendments to the instant claims.
17/932,226
Claims 21-22, 24-25, 27-28, 31, 34-35, and 37-38 remain provisionally rejected and claims 41 and 43 are newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 49-55 and 58 of copending Application No. 17/932,226 ('226) in view of Lundberg (US 2016/0333056 A1; cited in IDS) as evidenced by Walpole et al. (2012, BMC Public Health) and Möhlen (WO 2013/083726 A1; cited in IDS). This is a provisional nonstatutory double patenting rejection.
Regarding instant claims 21-22, 25, 28, 31, 35, and 38, the ‘226 claims teach a method of treating or preventing against a Borrelia infection in a subject, comprising administering to the subject a pharmaceutical composition comprising a mutant fragment of a Borrelia outer surface protein A (OspA) (‘226 claims 49, 53 and 58). The ‘226 claims also teach that the pharmaceutical composition may further comprise L-methionine and aluminum hydroxide (i.e., pharmaceutical composition is an aluminum composition) (‘226 claims 54-55). The ‘226 claims teach that the mutant OspA fragment may comprise Lip-S1D1-S2D1 (SEQ ID NO: 186), which is identical to instant SEQ ID NO: 1 (see alignment below) (‘226 claims 50-52).
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Alignment of instant SEQ ID NO: 1 (Qy) and the ‘226 claims’ SEQ ID NO: 186 (Db), both identified as Lip-S1D1-S2D1.
However, the ‘226 claims do not teach a method comprising administering an aluminum composition comprising less than 1.25 ppb copper to a human, as in instant claims 21-22 and 31, copper in the form of an ion, as in instant claims 24 and 34, a reactive compound, as in instant claims 21-22, 27, 31, and 37, a composition comprising the OspA heterodimer proteins of SEQ ID NOs: 1-3, as in instant claims 21-22 and 31, or the dosages of OspA heterodimer proteins recited in instant claims 21-22 and 31. The ‘226 claims are silent on the amount or concentration of L-methionine in the composition.
Regarding instant claims 21-22, 27, 31 and 37, Lundberg teaches a method comprising administering a pharmaceutical composition to a human (para. 198-199), wherein the pharmaceutical composition may comprises a polypeptide (i.e., a protein antigen), a L-methionine (i.e., a radical quenching compound) as a pharmaceutically acceptable excipient (para. 172-176 and 181), an aluminum adjuvant (para. 182), and polysorbate-20 as a stabilizing compound (i.e., a reactive compound) (para. 184). Lundberg teaches that polypeptide (i.e., protein antigen) of the composition may comprise Lip-S1D1-S2D1, Lip-S4D1-S3hybD1, and Lip-S5D1-S6D1, which have sequences given in SEQ ID NOs: 29, 27, and 33, respectively (para. 178 and 186), and are identical to instant SEQ ID NOs: 1-3, respectively (see alignments in Figures 1-3 above).
Regarding the limitation “a radical quenching compound which is L-methionine, in a molar concentration at least equivalent to the concentration of copper”, Lundberg teaches that the adjuvant used in the composition may be an aluminum adjuvant that makes a solution having less than 350 ppb heavy metal (e.g., copper); however, this concentration is not limited to a single metal, so it is assumed that the concentration of a single metal will be much lower than 350 ppb (para. 213). Lundberg’s preferred composition (para. 185) comprises 10 mM L-methionine (i.e., 0.01 mol/L), or 1.49 g/L (0.01mol/L *149.21 g/mol (molar mass of L-methionine) = 1.4921 g/L), which is greater than 350 ppb (i.e., 350 µg/L). Thus, the concentration of L-methionine in mol/L is greater than the concentration of copper in the composition.
Regarding the administration of OspA heterodimers, Lundberg teaches that the dosage for the vaccine may be between 0.02 µg and 3 µg antigen per kg body weight for adults and between 0.2 µg and 10 µg antigen per kg body weight for children (para. 220). For adults, this would result in a vaccine comprising between about 1.24 µg and 186 µg, based on the average adult weight of 62.0 kg (as evidenced by Walpole et al., Table 3). Lundberg also teaches that the dose may be administered from 1 to 3 times (para. 220).
Regarding instant claims 25 and 35, Lundberg teaches that the concentration of L-methionine may be 10 mM, i.e., 10 mmol/L (para. 185).
Regarding instant claims 28 and 38, Lundberg teaches that the Lip-S1D1-S2D1, Lip-S4D1-S3hybD1, and Lip-S5D1-S6D1 proteins are mixed at a molar ratio (i.e., weight ratio) of preferably 1:1:1 (para. 186).
Regarding instant claims 41 and 43, Lundberg teaches that the aluminum adjuvant may be aluminum hydroxide or aluminum phosphate (para. 182).
Regarding instant claims 21-22 and 31, Möhlen teaches that a protein composition (such as a vaccine comprising a protein antigen) preferably has less than 1 or 0.2 ppb copper, because the presence of copper affects the storage stability of the compositions (pg. 27, lines 19-30). Möhlen also teaches that the presence of heavy metals (including copper) in aluminum-adjuvanted compositions affects the shelf life of proteins containing proteins and that the degradation of proteins increases as time passes; therefore, reduced presence of heavy metals improves protein stability and shelf life (pg. 20, lines 9-27).
Regarding instant claims 24 and 34, Möhlen teaches that copper may be in the form of an ion (pg. 52, line 15, and pg. 70, line 8 – pg. 72, line 12).
Regarding instant claims 27 and 37, Möhlen teaches that the protein composition may further comprise a reactive compound, including a redox active compound, radical building compound, and/or a stabilizing compound (pg. 29, line 24 – pg. 30, line 9).
Therefore, it would have been prima facie obvious, to a person of ordinary skill in the art, to combine the pharmaceutical composition of the ’226 claims with the reactive compound and Lip-S4D1-S3hybD1 and Lip-S5D1-S6D1 heterodimers taught by Lundberg and administer the composition to a human using the dosage parameters taught by Lundberg, thereby arriving at the invention of claims 21-22, 25, 27-28, 31, 35, 37-38, 41, and 43. The person of ordinary skill in the art would have been motivated to make the modification because all elements taught by the ‘226 claims are taught by Lundberg and one would be motivated to use the parameters set forth by Lundberg to optimize the dosage of the vaccine based on the target population. Therefore, the combination is also desirable (see MPEP 2144(II)). The person of ordinary skill in the art would have had a reasonable expectation of success because Lundberg demonstrates that the elements taught by the ‘226 claims may be used in a vaccine and administered to a human. Therefore, the combination leads to expected results because each element performs the same function as is does individually.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, 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 that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, all elements (i.e., aluminum composition comprising L-methionine and reactive compound, Borrelia OspA heterodimer vaccine and dosages) were known in the art. In addition, combining these elements yields a method/composition wherein each element merely performs the same function as it does separately; thus, the results of the combination would be recognized as predictable to one of ordinary skill in the art. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Regarding the dosages of the OspA heterodimer proteins of instant claims 21-22 and 31, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985)) (see MPEP 2144.05.01). The courts have also found that “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). See MPEP 2144.05(II). Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Additionally or alternately, it would have been prima facie obvious, to a person of ordinary skill in the art, to further modify the composition to comprise less than 1.00 ppb copper as taught by Möhlen, thereby arriving at the invention of claims 21-22, 24-25, 27-28, 31, 34-35, 37-38, 41, and 43. The person of ordinary skill in the art would have been motivated to make the modification because Möhlen teaches that the presence of copper causes protein degradation, which affects the stability of the proteins in the composition and negatively impacts the shelf life and efficacy of the composition. Therefore, the combination is also desirable (see MPEP 2144(II)). The person of ordinary skill in the art would have had a reasonable expectation of success because Möhlen demonstrates that compositions containing less than 1.25 ppb copper show less protein degradation compared to those with higher copper and heavy metal concentrations. Therefore, the combination leads to expected results because each element performs the same function as is does individually.
Regarding the limitation, “an aluminum composition with increased antigen bioavailability”, where the claimed and prior art products are identical or substantially identical in structure or composition, … 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). Because the combination of Lundberg and Möhlen results in a method comprising administering a composition substantially identical to the aluminum composition of the instant claims (i.e., a composition comprising less than 1.25 ppb copper or L-methionine in a molar concentration at least equivalent to the concentration of copper, an aluminum adjuvant, at least one of the recited reactive compounds, and one of the recited protein antigens), the property of “increased antigen bioavailability” is presumed to be inherent to the combination product. "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).
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, 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 that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, all elements (i.e., aluminum composition comprising less than 1.25 ppb copper, aluminum composition comprising L-methionine and reactive compound, Borrelia OspA heterodimer vaccine and dosages) were known in the art. In addition, combining these elements yields a method/composition wherein each element merely performs the same function as it does separately; thus, the results of the combination would be recognized as predictable to one of ordinary skill in the art. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
US 11,466,058 B2
Claims 21-22, 24-25, 27-28, 31, 34-35, and 37-38 remain rejected and claims 41 and 43 are newly rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-10 of U.S. Patent No. 11,466,058 ('058) in view of Lundberg (US 2016/0333056 A1; cited in IDS) as evidenced by Walpole et al. (2012, BMC Public Health) and Möhlen (WO 2013/083726 A1; cited in IDS).
Regarding instant claims 21-22, 25, 28, 31, 35, 38, 41, and 43 the ‘058 claims teach a vaccine comprising Borrelia OspA fragments Lip-S1D1-S2D1 (SEQ ID NO: 186; identical to instant SEQ ID NO: 1) and Lip-S5D1-S6D1 (SEQ ID NO: 190; identical to instant SEQ ID NO: 3), aluminum hydroxide (i.e., an aluminum adjuvant), and L-methionine (‘058 claims 8-10).
However, the ‘058 claims do not teach a method comprising administering the aluminum composition to a human or an aluminum composition comprising less than 1.25 ppb copper, as in instant claims 21-22 and 31, copper in the form of an ion, as in instant claims 24 and 34, a reactive compound, as in instant claims 21-22, 27, 31, and 37, a vaccine comprising the OspA heterodimer proteins of SEQ ID NOs: 1-3, as in instant claims 21-22, 28, 31, and 38, or the dosages of OspA heterodimer proteins recited in instant claims 21-22 and 31. The ‘226 claims are silent on the amount or concentration of L-methionine in the composition.
The teachings of Lundberg with respect to instant claims 21-23, 25-29, 32-33, and 35-40 are set forth in the double patenting rejection over 17/932,226 above (para. 50-55).
The teachings of Möhlen with respect to instant claims 21-22, 24, 31, and 34 are set forth in the double patenting rejection over 17/932,226 above (para. 56-58).
Therefore, it would have been prima facie obvious, to a person of ordinary skill in the art, to combine the vaccine of the ’058 claims with the reactive compound and Lip-S4D1-S3hybD1 heterodimer taught by Lundberg and administer the composition to a human using the dosage parameters taught by Lundberg, and further modify the composition to comprise less than 1.00 ppb copper as taught by Möhlen, thereby arriving at the claimed invention.
The motivation and rationale for combining the teachings of the ‘058 claims with Lundberg and Möhlen is the same as that set forth in the double patenting rejection over 17/932,226 above (para. 59-64).
US 10,544,194 B2
Claims 21-22, 24-25, 27-28, 31, 34-35, and 37-38 remain rejected and claims 41 and 43 are newly rejected ground of nonstatutory double patenting as being unpatentable over claims 8-9 of U.S. Patent No. 10,544,194 ('194) in view of Lundberg (US 2016/0333056 A1; cited in IDS) as evidenced by Walpole et al. (2012, BMC Public Health) and Möhlen (WO 2013/083726 A1; cited in IDS).
Regarding instant claims 21-22, 25, 28, 31, 35, and 38, the ‘194 claims teach a vaccine comprising Borrelia OspA fragments Lip-S1D1-S2D1 (SEQ ID NO: 186; identical to instant SEQ ID NO: 1) and Lip-S5D1-S6D1 (SEQ ID NO: 190; identical to instant SEQ ID NO: 3), aluminum hydroxide (i.e., the vaccine is an aluminum composition), and L-methionine (‘194 claims 8-9).
However, the ‘194 claims do not teach a method comprising administering the aluminum composition to a human or an aluminum composition comprising less than 1.25 ppb copper, as in instant claims 21-22 and 31, copper in the form of an ion, as in instant claims 24 and 34, a reactive compound, as in instant claims 27 and 37, a vaccine comprising the OspA heterodimer proteins of SEQ ID NOs: 1-3, as in instant claims 28 and 38-40, or the dosages of OspA heterodimer proteins recited in instant claims 29 and 39-40. The ‘226 claims are silent on the amount or concentration of L-methionine in the composition.
The teachings of Lundberg with respect to instant claims 21-23, 25-29, 32-33, and 35-40 are set forth in the double patenting rejection over 17/932,226 above (para. 50-55).
The teachings of Möhlen with respect to instant claims 21-22, 24, 31, and 34 are set forth in the double patenting rejection over 17/932,226 above (para. 56-58).
Therefore, it would have been prima facie obvious, to a person of ordinary skill in the art, to combine the vaccine of the ’194 claims with the reactive compound and/or Lip-S4D1-S3hybD1 heterodimer taught by Lundberg and further modify the composition to comprise less than 1.00 ppb copper as taught by Möhlen, and administer the composition to a human using the dosage parameters taught by Lundberg, thereby arriving at the claimed invention.
The motivation and rationale for combining the teachings of the ‘058 claims with Lundberg and Möhlen is the same as that set forth in the double patenting rejection over 17/932,226 above (para. 59-64).
New Objection(s)
Claims 21, 42, and 44 are newly objected to because of the following informalities:
In claim 21, the scientific name “C. difficile” should be fully spelled out upon first use in the claims, and “the OspA heterodimer proteins are administered: to a human adult a protein content of… or to a human child a protein content of” are grammatically incorrect (a possible correction may be, e.g., “to a human adult with a protein content of” and “to a human child with a protein content of”, or addition of another appropriate preposition), and
In claims 42 and 44, the phrase “SEQ ID NO: 14 is does not include” should read “SEQ ID NO: 14 does not include”.
Appropriate correction is required.
New Rejection(s)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 112(b)
Claims 21-22, 28-30, 38-40, 42, and 44 are newly 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 21-22 and 31 each recite alternative protein antigens ((i)-(iii)) and administration dosages for antigen (i), OspA heterodimer proteins of SEQ ID NOs: 1-3. Claims 28-30, 38-40, 42, and 44, which depend upon claims 21-22 or 31, further limit the structure of the composition when it comprises antigens (ii) or (iii) (i.e., C. difficile fusion proteins or C. difficile toxin A and B proteins). Thus, it is unclear how the OspA heterodimer dosage limitations limit claims 21-22 and 31 if the aluminum composition comprises one of the other antigens and how the limitation affects the scope of claims 28-30, 38-40, 42, and 44 (e.g., are the OspA heterodimers still required to be administered when the composition comprises a different antigen?). Clarification is requested.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 42 and 44 are newly rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 42 and 44, which depend upon claims 22 and 31, respectively, recite “wherein the Clostridium difficile toxin A protein of SEQ ID NO: 13 and/or the Clostridium difficile toxin B protein of SEQ ID NO: 14 is does not include a histidine tag (His tag).” However, claims 22 and 31 recite “C. difficile toxin A protein of SEQ ID NO: 13 (Lip-ToxA-His) and/or a C. difficile toxin B protein of SEQ ID NO: 14 (Lip-ToxB-His)….” The limitation of claims 42 and 44 changes the structure of SEQ ID NOs: 13-14 by removing the His tag which makes up the last six residues of each of SEQ ID NOs: 13-14, thereby broadening the scope of protein structures. Therefore, claims 42 and 44 fail to limit the scope of claims 22 and 31 because they broaden the scope of the claims from which they depend.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
Claim(s) 21-22, 24, 27, 29-31, 34, 37, 39-41 and 43 are newly rejected under 35 U.S.C. 103 as being unpatentable over Ellingsworth et al. (US 10,357,557 B2; herein “Ellingsworth”) in view of Möhlen (WO 2013/083726 A1; cited in IDS).
Regarding claims 21-22 and 31, Ellingsworth teaches a method comprising administering to a human compositions comprising C-TAB.G5 (SEQ ID NO: 2, which is identical to instant SEQ ID NO: 7, see Figure 5 for alignment below) or C-TAB.G5.1 (SEQ ID NO: 4, which is identical to instant SEQ ID NO: 8, see Figure 6 for alignment below) (col. 4-5, paragraph bridging columns and col. 6, lines 20-24). Ellingsworth teaches that the composition may comprise an aluminum adjuvant (col. 5, lines 16-18), surfactants, such as TWEEN®80 (i.e., polysorbate; col. 54, lines 38-41), and antioxidants (i.e., radical quenching compound), such as methionine (col. 27, lines 54-67). Ellingsworth teaches that both C-TAB proteins confer protection against C. difficile A and B toxins when administered with an adjuvant (see FIGs. 6 and 13).
Regarding claims 29 and 39, Ellingsworth teaches that the dose of C-TAB.G5 or C-TAB.G5.1 comprises 20 to 200 µg of the protein (col. 5, lines 25-27).
Regarding claims 30 and 40, Ellingsworth teaches that the composition comprising C-TAB.G5 or C-TAB.G5.1 may be administered in a three dose regimen, wherein the second dose is administered around 7 days after the first dose, and the third dose is administered around 21 days after the first dose (col. 5, lines 33-24). Ellingsworth also teaches that suitable doses of C-TAB.G5 or C-TAB.G5.1 may be 20, 75, or 200 µg (col. 32, lines 52-54) and administered on days 0, 7, and 21, respectively (col. 53, lines 16-22).
Regarding claims 41 and 43, Ellingsworth teaches that the aluminum adjuvant may be aluminum hydroxide (col. 27, lines 49-50).
However, Ellingsworth does not teach a composition comprising less than 1.25 ppb of copper or L-methionine in a molar concentration at least equivalent to the concentration of copper or a composition comprising both C-TAB.G5 and C-TAB.G5.1 proteins, as in claims 21-22 and 31, copper in the form of an ion, as in claims 24 and 34.
The teachings of Möhlen with respect to claims 21-22, 24, 27, 31, 34, and 37 are set forth in para. 27-29 above.
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to modify the composition taught by Ellingsworth to comprise both C-TAB.G5 and C-TAB.G5.1 proteins and less than 1 ppb of copper, as is taught by Möhlen, thereby arriving at the invention of claims 21-22, 25, 27, 29-31, 35, 37, 39-41 and 43. The person of ordinary skill in the art would have been motivated to make the modifications to the composition because Ellingsworth teaches that both C-TAB proteins confer protection against C. difficile toxins A and B and Möhlen teaches that the presence of copper in adjuvanted compositions causes protein degradation, which affects the stability of the proteins in the composition and negatively impacts the shelf life and efficacy of the composition. Therefore, the combination is also desirable (see MPEP 2144(II)). The person of ordinary skill in the art would have had a reasonable expectation of successfully using both proteins because both C-TAB proteins are known to confer protection against C. difficile toxins. Additionally, one would have had a reasonable expectation of successfully administering a composition with less than 1 ppb of copper because Möhlen demonstrates that compositions containing less than 1.25 ppb copper show less protein degradation compared to those with higher copper and heavy metal concentrations. Therefore, the combination leads to expected results because each element performs the same function as is does individually.
Regarding the limitation, “an aluminum composition with increased antigen bioavailability”, where the claimed and prior art products are identical or substantially identical in structure or composition, … 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). Because the combination of Ellingsworth and Möhlen results in a method comprising administering a composition substantially identical to the aluminum composition of the instant claims (i.e., a composition comprising less than 1.25 ppb copper or L-methionine in a molar concentration at least equivalent to the concentration of copper, an aluminum adjuvant, at least one of the recited reactive compounds, and one of the recited protein antigens), the property of “increased antigen bioavailability” is presumed to be inherent to the combination product. "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).
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, 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 that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, all elements (i.e., method comprising administering a composition comprising aluminum adjuvant, polysorbate, and C-TAB.G5 and C-TAB.G5.1 proteins and adjuvanted compositions comprising less than 1 ppb of copper) were known in the art. In addition, combining these elements yields a method/composition wherein each element merely performs the same function as it does separately; thus, the results of the combination would be recognized as predictable to one of ordinary skill in the art. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
[AltContent: textbox (Figure 5: Alignment of instant SEQ ID NO: 7 (Qy) with Ellingsworth’s SEQ ID NO: 2 (Db).)]
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[AltContent: textbox (Figure 6: Alignment of instant SEQ ID NO: 8 (Qy) with Ellingsworth’s SEQ ID NO: 4 (Db).)]
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Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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 BAILEY M MORGAN whose telephone number is (703)756-5388. The examiner can normally be reached M-F 9-5 ET.
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/BAILEY M MORGAN/Examiner, Art Unit 1645
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1645