DETAILED ACTION
Acknowledgment and entry of the Amendment submitted on 9/9/26 is made.
Claims 1-20 are currently pending.
Claims 6-9 remain withdrawn for being drawn to a non-elected invention.
Claims 1-5, 10-15 and new claims 16-20 are currently under examination.
Allowable Subject Matter
Claims 5 and 12 are objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
NOTE: Claim 2 would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims and if the term “comprises” in lines 3 and 6 is changed to “consists of”.
Claim Rejections - 35 USC § 112-Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 3-4, 10, 11 and 13-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention is directed to immunogenic fusion proteins comprising a polypeptide with at least 90% sequence identity to SEQ ID NO: 7 an consisting of170-178 amino acids) and a polypeptide with at least 90% sequence identity to SEQ ID NO:14 (and with 165-174 amino acids) and methods of vaccination against group B streptococcus infection, or treating a group B Streptococcus infection comprising administering the immunogenic fusion protein comprising said immunogenic fusion proteins in a human or animal. Claim 11 recites the vaccine further comprises an amino acid having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 42.
To fulfill the written description requirements set forth under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative number of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. To adequately describe the genus of vaccines, Applicant must adequately describe the immunoepitopes within the polypeptide of SEQ ID NO: 7 and the polypeptide of SEQ ID NO:14 that induce a protective immune response against group B Streptococcus when part of a fusion protein. The specification, however, does not disclose distinguishing and identifying features of a representative number of members of the genus of vaccines (fusion proteins) to which the claims are drawn, such as a correlation between the structure of the fusion protein and its recited function (inducing a protective immune response against a given pathogen), so that the skilled artisan could immediately envision, or recognize at least a substantial number of members of the claimed genus of vaccines. Moreover, the specification fails to disclose which amino acid residues in the component proteins are essential for eliciting the claimed immune response, or which amino acids might be added, replaced or deleted so that the resultant component protein retains the immunological characteristics of its parent, or by which other amino acids the essential amino acids might be replaced so that the resultant component protein retains the immunological characteristics of its parent. Therefore, the specification fails to adequately describe at least a substantial number of members of the genus of fusion proteins to which the claims refer; and accordingly, the specification fails to adequately describe at least a substantial number of members of the claimed genus of vaccines. The term “vaccine” is defined as the use of a specific antigen to induce protective immunity to infection or disease induction. The specification does not provide substantive evidence that the claimed fusion proteins are capable of inducing protective immunity. This demonstration is required for the skilled artisan to be able to use the claimed vaccines for their intended purpose of preventing infections. Without this demonstration, the skilled artisan would not be able to reasonably predict the outcome of the administration of the claimed fusion proteins, i.e., would not be able to accurately predict if protective immunity has been induced. The ability to reasonably predict the capacity of a single bacterial immunogen to induce protective immunity from in vitro antibody reactivity studies is problematic. Ellis (Vaccines, W.B. Saunders Company, Chapter 29, 1988, pages 568-574) exemplifies this problem in the recitation that "the key to the problem (of vaccine development) is the identification of the protein component of a virus or microbial pathogen that itself can elicit the production of protective antibodies"(page 572, second full paragraph). Unfortunately, the art is replete with instances where even well characterized antigens that induce an in vitro neutralizing antibody response fail to elicit in vivo protective immunity. See Boslego et al (Vaccines and Immunotherapy, 1991, Chapter 17), wherein a single gonococcal pillin protein fails to elicit protective immunity even though a high level of serum antibody response is induced (page 212, bottom of column 2). Accordingly, the art indicates that it would require empirical testing to formulate and use a successful vaccine without the prior demonstration of vaccine efficacy.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed' ”. The courts have decided:
The purpose of the “written description” requirement is broader than to merely explain how to “make and use”; the applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the “written description” inquiry, whatever is now claimed.
See Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991). Furthermore, the written description provision of 35 USC § 112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
MPEP 2163.02 further states, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention” See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). Moreover, because the claims encompass a genus of variant species, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Additionally, MPEP 2163 states:
"A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)”
And:
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
As evidenced by the teachings of Skolnick et al., the art is unpredictable. Skolnick et al. (Trends in Biotechnology 18: 34-39, 2000) discloses the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based upon sequence homology is inaccurate, in part because of the multifunctional nature of proteins (see, e.g., the abstract; and page 34, Sequence-based approaches to function prediction). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan's best guess as to the function of the structurally related protein (see, in particular, the abstract and Box 2). Thus, one skilled in the art would not accept the assertion, which is based only upon an observed similarity in amino acid sequence that a variant of a given polypeptide would necessarily have a given immunological property. The instant specification has failed to teach or disclose vaccine compositions comprising the claimed fusion proteins that are protective against infections caused by group B Streptococcus. The specification fails to teach or disclose data that demonstrates that the claimed vaccines can provide protection against infections caused by group B Streptococcus. There is no disclosure of subjects that have been immunized with the claimed fusion proteins nor is there a disclosure of challenge studies that have been conducted to establish the claimed fusion protein’s ability to provide protection against a given pathogen. The specification merely refers to the use of the claimed fusion proteins in a general or prophetic sense but provides no real data. Consequently, there is no correlation between structure and function as required by the Written Description requirement. Moreover, the specification clearly demonstrates that the efficacy of all potential “vaccines” must be tested empirically when it states: “To determine whether protective immunity is induced by a fusion protein or vaccine, techniques well known for a person skilled in the art can be used. For example, to determine whether immunization with a given fusion protein induces protective immunity against a given pathogen (e.g., group B Streptococcus infection), immunized test animals can be challenged with a said pathogen and growth and spread of the group B Streptococcus is measured.” (see paragraph [0061] of the published specification).
With respect to 90% variants, to fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. Applicants have not described the genus of claimed variants such that the specification might reasonably convey to the skilled artisan that Applicants had possession of the claimed invention at the time the application was filed.
With the written description of a genus, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that "merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim's functional boundaries."). Abbvie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 U.S.P.Q.2d 1780, 1790, 2014 BL 183329, 12 (Fed. Cir. 2014).
To fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention.
The purpose of the "written description" requirement is broader than tomerely explain how to "make and use"; the applicant must convey with reasonableclarity to those skilled in the art that, as of the filing date sought, he or she was inpossession of the invention. The invention is, for purposes of the "writtendescription" inquiry, whatever is now claimed. See Vas-Cath, Inc. v. Mahurkar,935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).Furthermore, the written description provision of 35 USC § 112 is severable fromits enablement provision; and adequate written description requires more than amere statement that it is part of the invention and reference to a potential methodfor isolating it. The nucleic acid [product] itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention" (Id. at 1104). Moreover, because the claims encompass a genus of variant species, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. An objective standard for determining compliance with the written description requirement is, "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). To satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991) and MPEP 2163.02.
However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was "ready for patenting" by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus'" (Id. at 1106); accordingly, it follows that an adequate written description of a genus cannot be achieved in the absence of a disclosure of at least one species within the genus. The scope of the claim includes numerous structural variants, and the genus is highly variant because a significant number of structural differences between genus members is permitted.
There are no drawings or structural formulas disclosed of any of thesefragments or variants of the claimed fusion polypeptides There is no teaching in thespecification regarding which 10% of the structure can be varied and still produce a polypeptide which has the recited immunogenic properties. Although the disclosure of SEQ ID NOs: 7, 14 and 42 combined with the knowledge in the art, may put one in possession of peptides that are at least 90% identical to SEQ ID NO: 7, 14 and 42, the level of skill and knowledge in the art is such that one of ordinary skill would not be able to identify without further testing which of those peptides having at least 90% identity to SEQ ID No: 7 and 14 and produce a fusion polypeptide which has the ability to treat or prevent group B Streptococcus infection in a human or animal.
Based on the lack of knowledge and predictability in the art, those of ordinaryskill in the art would not conclude that the applicant was in possession of theclaimed genus of fusion polypeptides.
One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the claimed genus. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
Therefore, because the art is unpredictable, in accordance with the MPEP, the description of claimed fusion proteins is not deemed representative of the genus of fusion proteins to which the claims refer.
Response to Applicants’ arguments:
Applicants argue:
As regards to the use of the term vaccine, reference is made to Example 2 and Fig. 3 of the present specification, which shows the recited fusion protein having a protective effect on mice pups following neonatal bacterial infection with group B Streptococcus strain BM110. Specifically, mice pups born to female mice having been immunized with the immunogenic fusion protein of SEQ ID NO: 21 had significantly higher survival rate throughout the experiment (0 - 48 hours post infection) than the mice pups born from mothers receiving the control. The above example specifically refutes the statement in the office action that "There is no disclosure of subjects that have been immunized with the claimed fusion proteins nor is there a disclosure of challenge studies that have been conducted to establish the claimed fusion protein's ability to provide protection against a given pathogen." Accordingly, here also, it is respectfully submitted that the skilled artisan would conclude that a vaccine comprising the immunogenic fusion protein recited herein could be used for its intended purpose of preventing infections. Again, with reference to the cross reactivity of antibodies elicited by the recited immunogenic fusion protein, the skilled artisan would conclude that the vaccine variants encompassed by the claims would be useful for their intended purpose of preventing infections.
This has been fully and carefully considered but is not deemed persuasive because the argument is not commensurate in scope to the claims presently rejected under 112, first paragraph which allow for variant sequences up 90% without reciting structure critical to the functioning of the composition. See the rejection set forth above.
Applicants also argue that an earlier US Patent, e.g., US Patent No. 11,325,950, which is not part of the lineage of the instant application, shown that antibodies obtained by one antigen, e.g., Alp1, will cross-react and recognize another antigen, e.g., Alpha N. These arguments have been fully and carefully considered but are not deemed persuasive. The disclosure is not part of the instant specification and also does not provide insight into the required amino acids in the structures instantly claimed. Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: “Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” With the written description of a genus, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that "merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim's functional boundaries."). Abbvie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 U.S.P.Q.2d 1780, 1790, 2014 BL 183329, 12 (Fed. Cir. 2014).
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.
Claim(s) 1, 2, 3-4, 10, 11 and 13-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lindahl, G (US Patent No. 8,313,748; WO 2008/127179, 10/23/2008; US-20100062015A1), Pederson et al (WO 2017/068112; April 27, 2017; provided by Applicants) and Pederson et al (WO 2017/114655, July 6, 2017; provided by Applicants)
Notes: Newly amended instant claim 2 uses the open language “comprises” and recites:
The first amino acid sequence part comprises amino acids 1-175 of the sequence shown in SEQ ID NO: 7 or amino acids 2-175 of the sequence shown in SEQ ID NO: 7, and the second amino acid sequence part comprises amino acids 1-170 of the amino acids shown in SEQ ID NO: 14 or amino acids 2-170 of the sequence shown in SEQ ID NO: 14;
Instant claim 1 recites:
An immunogenic fusion protein comprising an amino acid sequence consisting of: i) a first amino acid sequence part consisting of 170-178 amino acids, and having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 7;
ii. a second amino acid sequence part consisting of 165-174 amino acids, and having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 14; and iii. a linker amino acid sequence part consisting of 1 to 20 amino acids and separating the first amino acid sequence part from the second amino acid part, and wherein the immunogenic fusion protein consists of 335 to 372 amino acids.
Instant claim 4 recites: the immunogenic fusion protein according to claim 1, wherein the immunogenic fusion protein has at least 90% sequence identity to SEQ ID NO: 21.
Lindahl, G (US Patent No. 8,313,748), Lindahl, G (WO 2008/127179; 10/23/2008) and Lindahl G. (US20100062015A1) all teach:
Lindahl teaches a S. agalactiae group B Rib-AlphaC fusion protein, shown in SEQ ID 6, which is 99.7% identical to Applicant’s SEQ ID NO: 21. Amino acids 33-378 from SEQ ID NO: 6 of Lindahl, match Applicant’s 2-347 of Applicant’s SEQ ID NO: 21.
Lindahl also teaches a first amino acid (SEQ ID NO: 2) which is 179 amino acids in total length and 99.4% identical to Applicant’s SEQ ID NO: 7 (zero mismatches/substitutions).
Lindahl also teaches a second amino acid (SEQ ID NO: 4) which is 175 acids in total length and 100% identical to the full-length of Applicant’s SEQ ID NO: 14 (amino acids 1-170).
The Lindahl references teach methods of vaccinating vertebrates to treat and/or prevent Group B streptococcus infections. It is taught the fusion protein vaccines may be administered to humans or animals, including mammals and birds, such as rodents (mouse, rat, guinea pig, or rabbit); birds (turkey, hen or chicken); other farm animals (cow, horse, pig or piglet); pets (dog, cat and other pets); and humans. While many animals may be treated with the preparation of the invention, a preferred individual for treatment is a human or commercially valuable animal and livestock. See paragraphs 76-87. Vaccination of females, e.g., mothers is specifically taught.
Pederson et al (WO 2017/068112; 4/27/17; provided by Applicants) discloses an immunogenic fusion protein (SEQ ID NO:6) comprising the N- terminal domains of two Streptococcal proteins (Rib and AlpC). Pederson teaches SEQ ID NO: 12 which is 100% identical to Applicant’s SEQ ID NO: 42. Pederson discloses an first amino acid sequence having at least 80% identity with the N-terminal region of a Rib protein and a second sequence at least 80% identical to an AplC protein. See claims, for example.
Pederson et al (WO 2017/114655, 7/6/17; provided by Applicants) discloses an immunogenic fusion protein (SEQ ID NO:6) comprising the N- terminal domains of two Streptococcal proteins (Rib and AlpC) for use in combination with a bacterial polysaccharide. Pederson teaches SEQ ID NO: 12 which is 100% identical to Applicant’s SEQ ID NO: 42. Pederson discloses an first amino acid sequence having at least 80% identity with the N-terminal region of a Rib protein and a second sequence at least 80% identical to an AplC protein. See claims for example.
Accordingly, Lindahl’s Rib first portion is 179 amino acids in length (not 170-178) and Lindahl’s second AlpC portion is 175 amino acids in length (not 165-174), yet the fusion of these portions in Lindahl is 354 total amino acids in length, e.g., within the range of 335-372. Lindhal’s SEQ ID NO: 6 fusion protein in 378 amino acids in length. All references teach the use of an adjuvant with the fusion protein. Claims 16 and 17 of Pederson ‘112 and claims 19 and 20 of Pederson ‘655 specifically teach the use of aluminum hydroxide.
Accordingly, Lindahl does not explicitly recite a Rib-AlpC fusion protein comprising a Rib and AlpC sequences of the recited length, the ambiguity of the claim languages makes it obvious in view of the teachings of Lindahl that a very significant portion and variants of those portion, e.g., up to 90% are acceptable, and just 1 amino acid longer than Applicant’s SEQ ID NO: 7 and just 5 amino acids longer than Applicant’s SEQ ID NO: 14. Pederson et al teach fusions between the N-terminal region of Rib and AlpC with variations of up to 80%.
It would have been prima facie obvious to one of ordinary skill in the art to provide an immunogenic fusion protein comprising N-terminal sequences from the two streptococcal proteins, Rib and AlpC. Instant Claim 1 does not state which sequences from SEQ ID NO:7 and 14 are to be used, and they are only 90% identical, so no effects can be assumed. The linker sequence in the claims is optional. However, the features a linker to connect two polypeptides in a fusion protein is routine in the art. The differences are considered mere arbitrary variations that the skilled person could select; the linker is in any case known from Pederson in SEQ ID NO:6 . Lindahl teaches a S. agalactiae group B Rib-AlphaC fusion protein, shown in SEQ ID 6, which is 99.7% identical to Applicant’s SEQ ID NO: 21. Amino acids 33-378 from SEQ ID NO: 6 of Lindahl, match Applicant’s 2-347 of Applicant’s SEQ ID NO: 21. Pederson et al teach fusions between the N-terminal region of Rib and AlpC with variations of up to 80%. One additional amino acid from Rib and up to 5 from AlpC would have been obvious variations according the prior art teachings in the art. No unexpected results have been shown and the instant claim does not even recite which particular amino acids are to be included in the claimed fusion proteins.
Response to Applicants’ arguments:
Applicants argue:
Examples 4 and 5 of the present specification demonstrate that truncating the leading amino acids of the fusion protein of Lindahl (SEQ ID NO: 6) to obtain a shorter fusion protein, e.g. SEQ ID NO: 21, leads to less screening of a region of the protein that is both evolutionary conserved and involved when GBS bacteria infect cells using the Rib surface protein. Accordingly, there is a clear technical effect of fully or partially truncating these leading amino acids so that the relevant region of the N-terminal of Rib included in the fusion protein of claim 1 is more accessible to the immune system of the host receiving the fusion protein as a vaccine against GBS. Further, as also noted in Table 1 and on page 31 of Applicant's specification, the interactions between the leading sequence and the various parts of the region of Rib occur at different amino acids of the leading sequence. Accordingly, the truncation of the fusion protein of Lindahl will provide a decreased interaction and better access with the immune system of a subject receiving the immunogenic protein. Similarly, a minor shortening and/or a removal of a lesser number of amino acids of the leading sequence will provide better access to the immune system for the RibN domain of the recited immunogenic fusion protein. That the Rib protein is indeed required for cell infection is supported by Panel A of Fig 5 of Lindahl which shows that a Rib negative mutant had significantly lowered ability to invade epithelial cells. This relevance for cell infection was also shown by Example 5 and Fig 6 of the current specification which show how this specific region of RibN is involved when the Rib protein interacts with α1ß1-integrin for adhesion and invasion of epithelial cells. Accordingly, it is respectfully submitted the present claims are patentable over Lindahl. In particular, a person of ordinary skill in the art with knowledge of Lindahl would not find any guidance in Lindahl prompting a truncation of an initial part of the fusion protein according to SEQ ID NO: 6. The skilled artisan reviewing Lindahl would have no reason to expect that a shorter fusion protein could provide an improved effect vis-a-vis SEQ ID NO: 6 of Lindahl. Pederson fails to remedy the deficiencies of Lindahl, no matter how the references may be combined. The Office asserts that "Pederson et al teach fusions between the N-terminal region of Rib and AlpC with variations of up to 80%." (Office Action, p. 18.) Even if this characterization of Pederson is correct, which Applicant does not necessarily concede, as noted above in detail, Lindahl fails to disclose or suggest reducing the number of amino acids in its leading sequence will provide enhanced access of the Rib portion of the recited immunogenic fusion protein to the immune system of a subject to which the immunogenic fusion protein is administered. Nowhere does Pederson provide such a teaching, i.e., Pederson fails to disclose or suggest reducing the number of amino acids in its leading sequence will provide enhanced access of the Rib portion of the recited immunogenic fusion protein to the immune system of a subject to which the immunogenic fusion protein is administered. Thus, Pederson fails to remedy the deficiencies of Lindahl.
These arguments have been fully and carefully considered but are not deemed persuasive as they are not commensurate in scope with the claimed invention. The claims drawn to SEQ ID NO: 21 are not included in the instant rejection. It would have been prima facie obvious to one of ordinary skill in the art to provide an immunogenic fusion protein comprising N-terminal sequences from the two streptococcal proteins, Rib and AlpC. Instant Claim 1 does not state which sequences from SEQ ID NO:7 and 14 are to be used, and they are only 90% identical, so no effects can be assumed. The features of a linker to connect two polypeptides in a fusion protein is routine in the art. The differences are considered mere arbitrary variations that the skilled person could select; the linker is in any case known from Pederson in SEQ ID NO:6 . Lindahl teaches a S. agalactiae group B Rib-AlphaC fusion protein, shown in SEQ ID 6, which is 99.7% identical to Applicant’s SEQ ID NO: 21. Amino acids 33-378 from SEQ ID NO: 6 of Lindahl, match Applicant’s 2-347 of Applicant’s SEQ ID NO: 21. Pederson et al teach fusions between the N-terminal region of Rib and AlpC with variations of up to 80%. One additional amino acid from Rib and up to 5 from AlpC would have been obvious variations according the prior art teachings in the art. No unexpected results have been shown and the instant claim does not even recite which particular amino acids are to be included in the claimed fusion proteins. A difference of a single amino acid on the end appears to be a routine optimization in the linker art. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). Since Applicant has not disclosed that the specific limitations are for any particular purpose or solve any stated problem (other than the fusion protein of SEQ ID NO: 21) and the prior art teaches that methods often vary according to the various linkers, solutions and parameters appear to work equally as well, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable size ranges of fusion proteins of the prior art by normal optimization procedures known in the art.
Status of Claims:
No claim is presently allowed.
An immunogenic fusion polypeptide consisting of the amino acid sequence of SEQ ID NO: 21 is free of the prior art. Claims 5 and 12 would be allowable if rewritten in independent form and if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
NOTE: Claim 2 would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims and if the term “comprises” in lines 3 and 6 is changed to “consists of”.
Amino acids 33-378 from SEQ ID NO: 6 of Lindahl, match Applicant’s 2-347 of Applicant’s SEQ ID NO: 21. The instant claims do not require the leading sequence (SEQ ID NO: 43) to be removed as shown in Applicant’s SEQ ID NO: 21. The instant claims allow for any amino acids, e.g., in any position, from SEQ ID NO: 7 and 14, as well as variants of up to 90%; however, the working examples in the specification utilize SEQ ID NO: 21.
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.
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/JENNIFER E GRASER/Primary Examiner, Art Unit 1645 9/18/26
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