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 .
Election/Restrictions
Applicant's election with traverse of Group I (i.e., claims 18-35 drawn to a Tau peptide immunogen construct) in the reply filed on June 30, 2026, is acknowledged. Additionally, Applicant's election with traverse of Species A (i.e., a construct comprising SEQ ID NO: 35 as the Th helper epitope, SEQ ID NO: 115 as the Tau fragment, ƐK-KKK as the A component, -COOH as the X component, m is 1, n is 1, and Th-A-Tau-X as the construct orientation thereby resulting in SEQ ID NO: 144) in the reply filed on June 30, 2026, is acknowledged (NOTE: election of SEQ ID NO: 115 instead of SEQ ID NO: 17 was obtained via a telephonic interview as indicated in the accompanying Interview Summary). The traversal is on the ground(s) that the claimed method of claim 36-38 is specifically tied to, and relies on, the claimed peptide construct of claims 18-35, and the application does not establish that the process is practiced with a materially different product or that the claimed conjugate is used in a materially different process (See Applicant’s Response received on 7/30/26, pg. 2). Moreover, the method claims do not create a serious search or examination burden or show patentable distinctness (See Applicant’s Response received on 7/30/26, pg. 2).
This is not found persuasive because the restriction mailed on 3/30/26 clearly states that the claimed conjugate is used in a materially different process, i.e., generating antibodies against the epitopes in the Tau immunogen construct (See Restriction mailed on 3/30/26, paragraph 2). As such, the restriction clearly provides a rationale as to why the inventions of instant Groups I and II are independent and distinct pursuant to MPEP 806.05(h). Furthermore, the Restriction indicates that a serious search and/or examination burden is present because the inventions of Groups I and II are classified separately, i.e., Group I is classified in C07K 14/4711 and Group II is classified in A61P 25/28 (See Restriction mailed on 3/30/26, paragraphs 1 and 2). As such, a serious search and/or examination burden exists. Thus, contrary to Applicants’ arguments, the inventions between Groups I and II do create a serious search and/or examination burden and show patentable distinctness.
The requirement is still deemed proper and is therefore made FINAL.
Please note that Applicants elected species of tau peptide immunogen construct (i.e., SEQ ID NO: 144) is free of the prior art. It is noted that there is no teaching or suggestion to utilize a tau fragment that “is” (i.e., consisting of) SEQ ID NO: 115. When expanding the scope of claim 32, it is noted that similar to elected SEQ ID NO: 144, SEQ ID NOs: 136 and 140-141 are also free of the prior art. Thus, the Species is expanded as further articulated below in the 103 rejection. Furthermore, it is noted that the orientation of the construct in Species A is withdrawn in light of the Examiner’s search.
Status of Claims
Claims 1-17 were originally filed on October 2, 2023.
The amendment received on October 2, 2023, canceled claims 2 and 6; and amended claims 1, 3, 5, 11-12, 14, and 16-17. The amendment received on August 5, 2024, canceled claims 1, 3-5, and 7-17; and added new claims 18-38.
Claims 18-38 are currently pending and claims 18-19, 21-24, and 26-35 are under consideration as claims 36-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, and claims 20 and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on July 30, 2026.
Priority
The present application is a continuation of U.S. Application No. 16/759,584, filed on April 27, 2020, now issued as U.S. Patent No. 11,773,148 B2, which claims status as a 371 (National Stage) of PCT/US2018/057840 filed October 26, 2018, and claims priority under 119(e) to U.S. Provisional Application No. 62/578,124 filed on October 27, 2017.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on October 2, 2023; August 5, 2024; and May 2, 2025, are being considered by the examiner.
Sequence Interpretation
For claim 18, please note that the Examiner is interpreting the scope of the tau peptide immunogen construct as open-ended, but with the following constraints. With respect to the Th component, it is noted that the Th sequence is limited to 100% identity and the same length to SEQ ID NO: 35 (i.e., Th “is” a heterologous T helper epitope of SEQ ID NO: 35), but this sequence can be repeated from 1-4 times (i.e., m is from 1 to 4). With respect to the “A” component, it is noted that “A” is limited to 100% identity and same length one of the recited spacer moieties (i.e., A “is” a heterologous spacer…) in the Markush group, but the “A” component can be absent (i.e., n is 0) or repeated up to 10 times (i.e., n is from 0 to 10). However, as further articulated in the 112(b) rejection below, it is unclear what moieties are encompassed by the Markush group. With respect to the tau fragment, it is noted that the sequence requires 100% identity to SQ ID NO: 115 (note: has a length of 15 total amino acids) with any N- and/or C-terminal additions up to where the sequence has a total of 40 amino acids. As such, the tau fragment can contain up to an additional 35 residues. With respect to the “X” component, it is noted that the C-terminus of the construct, whether the C-terminal component is the Th or tau fragment, is natural (i.e., α-COOH or amidated).
For claims 21 and 26, please note that the Examiner is interpreting the scope as closed-ended requiring 100% identity and the same length to SEQ ID NO: 115 (i.e., the B cell epitope “is” of the amino acid sequence of SEQ ID NO: 115). Thus, the scope of claims 21 and 26 limits the tau fragment component in the construct of claims 18 and 24, respectively, to SEQ ID NO: 115.
For claims 22 and 28, please note that the Examiner is interpreting the scope as closed-ended requiring 100% identity and the same length to one of the recited spacer moieties.
For claims 23 and 29, please note that the Examiner is interpreting the scope as closed-ended requiring 100% identity and the same length to the recited spacer moiety.
For claim 24, please note that the Examiner is interpreting the scope as open-ended, but with the following constraints. With respect to the B cell epitope, it is noted that the sequence requires 100% identity to SQ ID NO: 115 (note: has a length of 15 total amino acids) with any N- and/or C-terminal additions up to where the sequence has a total of 40 amino acids. As such, the tau fragment can contain up to an additional 35 residues. With respect to the T helper epitope, it is noted that the sequence requires 100% identity to SEQ ID NO: 35 with any N- and/or C-terminal additions (note: no transitional phrase limiting the T helper epitope to SEQ ID NO: 35). As such, the construct of claim 24 only requires two components; namely, the B cell epitope and the T helper epitope. The two required components are covalently linked directly or through a linker.
For claim 27, it is noted that “A” is limited to 100% identity and same length one of the recited spacer moieties (i.e., A “is” a heterologous spacer…) in the Markush group. However, as further articulated in the 112(b) rejection below, it is unclear what moieties are encompassed by the Markush group.
For claim 32, please note that the Examiner is interpreting the scope as closed-ended requiring 100% identity and the same length to one of the recited sequences. Please note that elected SEQ ID NO: 144 contains the following structure: SEQ ID NO: 35 - Ɛ-N-Lys-Lys-Lys- SEQ ID NO: 115 (note: X is α-COOH, m is 1 and n is 1). SEQ ID NO: 131 is identical to elected SEQ ID NO: 144 except where the tau fragment contains three additional residues at the N-terminus, i.e., KDN. SEQ ID NO: 136 is identical to elected SEQ ID NO: 144 except for where the tau fragment is SEQ ID NO: 19 with a total of 37 amino acids. SEQ ID NO: 140 is identical to elected SEQ ID NO: 144 except the proline residue at position 28 is indicated to be in the “trans” configuration. The instant specification teaches that the proline position corresponding to tau position 301 is incorporated in the trans conformation (See instant, pg. 46, 2nd paragraph). Although SEQ ID NO: 144 does not indicate whether the peptide bond of the proline residue at position 28 is in the cis or trans configuration, since the trans configuration is favored chemically over the cis configuration, it is interpretated that the two sequences are identical structurally. SEQ ID NO: 141 is identical to elected SEQ ID NO: 144 except it reverses the construct order of components; namely, SEQ ID NO: 115 - Ɛ-N-Lys-Lys-Lys- SEQ ID NO: 35.
Claim Objections
Claims 18, 22-23, and 27-29 are objected to because of the following informalities: the claims recite where the spacer moiety can be “Ɛ-N-Lys-Lys-Lys-Lys”. Pursuant to MPEP 2422 and 37 CFR 1.821(a), any amino acid sequence with at least 4 defined amino acids in length requires a sequence identifier. Additionally, please update the Sequence Listing, if necessary. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 18-19, 21, and 27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Pursuant to MPEP 2173.04 and 2173.02(I), a genus claim that could be interpreted in such a way that it is not clear which species are covered would be indefinite (e.g., because there is more than one reasonable interpretation of what species are included in the claim). As such, given the multiple claim interpretations of claim 1, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the presently claimed invention. In the instant case, claims 18 and 27 are directed to a heterologous spacer “selected from one or more amino acids, Lys, Gly,… The italicized portion encompasses multiple interpretations. The first interpretation is where the Markush group encompasses where the heterologous spacer is one or more amino acids, e.g., any number of amino acids and/or amino acid composition. As such, this interpretation encompasses where the Markush group includes one or more amino acids as a component of the Markush group. The second interpretation is where the “one or more amino acids” is part of the Markush transitional phrase, i.e., “selected from one or more amino acids:”, instead of being a component or option of the spacer. Since there are multiple reasonable interpretations for “one or more amino acids”, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the presently claimed invention.
Please note that the Examiner is interpretation the scope of claims 18 and 27 such that the second interpretation is applied in order to advance prosecution, i.e., the transitional Markush phrase contains “one or more amino acids”. It is suggested for the Markush group to be amended to recite, “ selected from the group consisting of: Lys-, Gly-,…., Ɛ-N-Lys-Lys-Lys-Lys, and combinations thereof.” Also please note that claims 19 and 21 are rejected by virtue of their dependency.
Claims 32 and 35 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 32 is directed to where the construct is SEQ ID NOs: 131, 136, 140-141, or 144. As discussed in the “Sequence Interpretation” section supra, SEQ ID NOs: 140 and 144 contain identical residues. In the Sequence Listing, there is a note for residues 24-38 for SEQ ID NO: 140, which corresponds to the tau fragment component of the construct that the proline residue at position 28 (i.e., corresponds to position 301 in the tau protein) is in the trans conformation. However, there is no indication for SEQ ID NO: 144, which conformation the proline residue is in, i.e., trans or cis. Therefore, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the presently claimed invention with respect to whether the structure of SEQ ID NOs: 140 and 144 is identical or distinct.
Please note that the Examiner is interpreting that SEQ ID NOs: 140 and 144 are structurally identical in order to advance prosecution because (1) a trans conformation is favored chemically in nature (See Pettitt et al. teaching: most peptide bonds within proteins exist almost exclusively in the energetically favorable trans conformation, Biophysical J. 123:3798-3811 (2024) at pg. 3799, col. 1, 2nd paragraph), and (2) the instant specification teaches that the proline position corresponding to tau position 301 is incorporated in the trans conformation (See instant, pg. 46, 2nd paragraph). Also please note that claim 35 is rejected by virtue of its dependency.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The 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.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 18-19, 22, 24, 27-28, 30-31, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Novak et al. US Patent No. 9,518,101 B2 issued on December 13, 2016, in view of Wang US Patent No. 7,951,909 B2 issued on May 31, 2011 (cited in the IDS received on 10/2/23).
For claims 18-19, 22, 24, 27-28, 30-31, and 33, ‘101 teaches immunogenic peptides that can be expressed as fusion proteins with carriers where the peptide can be linked at the amino terminus, the carboxyl terminus or at a site anywhere within the peptide (internally) to the carrier (See ‘101, col. 14, 2nd paragraph; col. 64, 2nd paragraph). For example, ‘101 teaches immunogens that include fusion proteins comprising a tau peptide carrying a protective B cell epitope linked to a promiscuous non-natural Pan DR Th-cell epitope that induces a B-cell responses against the protective epitope (See ‘101, col. 64, 3rd paragraph) thereby constituting the instant immunogen construct (note: analogous to a fusion protein) as recited in instant claims 18 and 24, and constituting where the carrier (e.g., a T helper epitope as further articulated below) is covalently linked to the carboxyl or amino termini of the immunogenic peptide (e.g., a B cell epitope as further articulated below) as recited in instant claims 30-31. It is further noted that the fusion proteins of ‘101 do not require that the Tau fragment free termini is natural, i.e., not modified. As such, it would necessarily follow that when the Tau fragment is fused to the carrier at the Tau fragment’s N-terminus thereby leaving the C-terminus free, the C-terminus is the natural α-COOH. Moreover, ‘101’s fusion protein teaches that one T helper epitope is fused to the Tau fragment and there is one spacer moiety. Thus, the teachings of ‘101 satisfy the claim limitations with respect to where instant X is α-COOH, m is 1 and n is 1 as recited in instant claims 18-19.
With respect to a Tau fragment being a B cell epitope comprising SEQ ID NO: 115 and having a length of 15 to 40 amino acid residues, ‘101 teaches that tau fragments that are active in inducing an immune response to pathological tau thereby constituting immunogenic tau fragments where the fragments are any one of SEQ ID NOs: 36-50 and are 30 amino acid residues in length (See ‘101, col. 56, 3rd paragraph; SEQ ID NOs: 36-50 in Table 1). It is noted that each of SEQ ID NOs: 36-50 contain instant SEQ ID NO: 115. As such, the tau immunogenic fragment of ‘101 are exemplary immunogenic peptides of ‘101’s fusion proteins. As discussed supra, the fusion proteins comprises a tau peptide carrying a protective B cell epitope. Thus, a tau fragment of any one of SEQ ID NO: 36-50 constitutes the instant Tau fragment that is a B cell epitope comprising instant SEQ ID NO: 115 and having 15 to 40 total residues in length as recited in instant claims 18, 24, and 33.
With respect to the Th being a T helper epitope of SEQ ID NO: 35, it is noted that SEQ ID NO: 35 is an immunogenic epitope derived from measles, i.e., MvF5. As discussed supra, ‘101 teaches that the carrier can be a promiscuous non-natural Pan DR Th-cell epitope that induces B-cell response against the protective epitope. Alternatively, the carrier can be a keyhole limpet hemocyanin (KLH), tetanus toxoid, bovine serum albumin, immunoglobulin molecule, thyroglobulin, or ovoglobulin (See ‘101, col. 64, 4th paragraph). ‘101 also teaches that the immunogenic peptide can be bound to a moiety where the moiety (in addition to the carrier description) can be a universal T-cell epitope (See ‘101, col. 14, 2nd paragraph). ‘101 defines a universal T-cell epitope as a sequence selected from influenza hemagluttinin (HA307-319), PADRE, Malaria CS:T3 epitope, Hepatitis B surface antigen, heat shock protein 65, bacille Calmette-Guerin, tetanus toxoid, and HIV gp120T1 (See ‘101, col. 33, 1st paragraph). Thus, the teachings of ‘101 satisfy the claim limitation with respect to where the tau fragment is fused to a T-cell or T-helper epitope as recited in instant claims 18, 24, and 33. However, ‘101 does not expressly teach where the T-helper epitope is MvF5 with an amino acid sequence of SEQ ID NO: 35.
‘909 teaches peptide immunogens that are represented by the formula: (A)n – (Th)m – (B)o – (N-terminal fragment of Aβ1-42 peptide) – X where A is independently an amino acid, B is a linking group such as (α, Ɛ-N)Lys, Th comprises an amino acid sequence that constitutes a helper T cell epitope, (N-terminal fragment of Aβ1-42 peptide) is a synthetic peptide B cell target site antigen and is a fragment of about 10 to about 28 amino acid residues where each fragment comprises EFRH of the Aβ1-42 peptide, X is a α-COOH or α-CONH2 of an amino acid, n is from 0 to about 10, m is from 1 to about 4, and o is from 0 to about 10 (See ‘909, col. 10, last paragraph to col. 11, 1st paragraph). The Th epitopes includes those derived from foreign pathogens including those depicted in Tables 1-2 (See ‘909, col. 12, 2nd paragraph). Preferred peptide immunogen fusion proteins utilize a Th epitope selected from HBsTh, HBcTh, MVF Th, PT Th, TT Th, CT Th, DT Th, MVF Th derived artificial Th of SEQ ID NOs: 38-10 and 47-51, and HBV Th derived from artificial Th of SEQ ID NOs: 52-54 (See ‘909, col. 12, 4th paragraph). As depicted in Table 1, the HBs Th sequence is a hepatitis B antigen where the sequence comprises the Hepatitis B surface antigen taught by ‘101 (note: ‘909’s SEQ ID NO: 1 contains ‘101’s Hepatitis B surface antigen (i.e., FFLLTRILTIP)); the TT Th sequences are tetanus toxoid sequences that contain overlapping residues with the ‘101 TT Th sequences (See ‘909, col. 20-21, Table 1). Moreover, it is noted that ‘101’s SEQ ID NO: 51 as a MvF Th epitope sequence as depicted in Table 2 (See ‘909, col. 22, Table 2) is 100% identical to instant SEQ ID NO: 35. Given that ‘909 teaches utilizing Th epitopes in a tau immunogenic construct where the epitopes preferably include tetanus toxoid, Hepatitis B surface antigen, and MvF5 thereby suggestive that each epitope functions in a similar manner, an ordinary skilled artisan would substitute the MvF5 Th epitope of instant SEQ ID NO: 35 as the universal T-cell epitope of ‘101 as further articulated below.
With respect to where the Tau fragment is covalently fused to the Th epitope via a spacer, ‘101 teaches embodiments where the immunogenic tau peptide is fused to the carrier epitope via a cleavable linker or cleavage site for proteinases, which can be called spacer moieties (See ‘101, col. 52, 2nd paragraph). Alternatively, the immunogenic peptides can be linked to carried by chemical crosslinking, for example, by using a cysteine residue as a spacer to form a disulfide bond, or using a moiety to form an amide bond (See ‘101, col. 64, 1st paragraph). Thus, the teachings of ‘101 satisfy the claim limitation with respect to where the instant Tau fragment is fused to the T helper epitope via a heterologous spacer as recited in instant claims 18, 24, 27, 30-31, and 33. However, ‘101 does not expressly teach where the spacer moiety is (α, Ɛ-N)Lys.
As discussed supra, ‘909 teaches peptide immunogens that are represented by the formula: (A)n – (Th)m – (B)o – (N-terminal fragment of Aβ1-42 peptide) – X where A is independently an amino acid, B is a linking group such as (α, Ɛ-N)Lys, Th comprises an amino acid sequence that constitutes a helper T cell epitope, (N-terminal fragment of Aβ1-42 peptide) is a synthetic peptide B cell target site antigen and is a fragment of about 10 to about 28 amino acid residues where each fragment comprises EFRH of the Aβ1-42 peptide, X is a α-COOH or α-CONH2 of an amino acid, n is from 0 to about 10, m is from 1 to about 4, and o is from 0 to about 10 (See ‘909, col. 10, last paragraph to col. 11, 1st paragraph). Broadly, ‘909 teaches that the spacer is an amino acid which can be naturally occurring or non-naturally occurring amino acids such as Gly-Gly, (α, Ɛ-N)Lys, Pro-Pro-Xaa-Pro-Xaa-Pro (See ‘909, col. 11, 4th paragraph). These immunogen constructs are stable and chemically made for easy quality control where no elaborate downstream processing nor an elaborate manufacturing facility is needed (See ‘909, col. 9, 2nd paragraph). Thus, the teachings of ‘909 demonstrate that an immunogenic tau fragment can be fused to a T helper epitope via a spacer such as (α, Ɛ-N)Lys as recited in instant claims 18, 22, 24, and 27-28.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of ‘101 and substitute instant SEQ ID NO: 35 as the universal T cell epitope instead of a tetanus toxoid or hepatitis B surface antigen, and substitute (α, Ɛ-N)Lys as the spacer moiety instead of Cys thereby forming a tau immunogen construct with the structure SEQ ID NO: 35 as a Th epitope - (α, Ɛ-N)Lys – Tau fragment containing instant SEQ ID NO: 115 in order to protect the tau fragment from degradation and thereby allowing the tau fragment to induce an immune response. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because immunogen tau fragments were known to be fused to a Th epitope such as MvF5 with a sequence of instant SEQ ID NO: 35, a tetanus toxoid, or a hepatitis B surface antigen where these immunogen constructs were known to be stable and chemically made for easy quality control where no elaborate downstream processing nor an elaborate manufacturing facility is needed as taught by ‘909. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the immunogen construct of ‘101 comprised a universal T cell epitope such as a tetanus toxoid or hepatitis B surface antigen – spacer moiety such as cysteine or a moiety forming an amide bond – tau fragment containing instant SEQ ID NO: 115 in order to protect the tau immunogenic peptide and induce an immune response. Therefore, substituting SEQ ID NO: 35 instead of a tetanus toxoid or hepatitis B surface antigen as the universal T cell epitope and substituting (α, Ɛ-N)Lys as the spacer moiety instead of cysteine would support the tau immunogenic construct being stable and chemically made for easy quality control where no elaborate downstream processing nor an elaborate manufacturing facility by constituting the simple substitution of one known element for another to obtain predictable results and/or the use of known technique to improve similar devices (methods, or products) in the same way and/or the application of a known technique to a known device (method, or product) ready for improvement to yield predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
For claim 33, ‘101 teaches that the agents of the invention can be administered as pharmaceutical formulations comprising a therapeutic agent, e.g., an immunogenic peptide, and one or more of other pharmaceutically acceptable components such as pharmaceutically acceptable excipients (See ‘101, col. 66, 1st to 2nd paragraphs). Additionally and/or alternatively, ‘101 teaches that the therapeutic agents or immunogens can be administered in combination with adjuvants (See ‘101, col. 66, last paragraph). Thus, the teachings of ‘101 satisfy the claim limitation with respect to a pharmaceutical composition comprising a pharmaceutically acceptable delivery vehicle and/or adjuvant as recited in instant claim 33.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Novak et al. US Patent No. 9,518,101 B2 issued on December 13, 2016, in view of Wang US Patent No. 7,951,909 B2 issued on May 31, 2011 (cited in the IDS received on 10/2/23), and further in view of Bode et al., Expert Rev. Vaccine 10:499-511 (2011).
For claim 34, with respect to the (a) component of the Tau peptide immunogen construct of claim 28 and (b) a pharmaceutically acceptable delivery vehicle and/or adjuvant, please see discussion of ‘101 and ‘909 supra.
With respect to where the Tau peptide immunogen construct is mixed with an CpG oligodeoxynucleotide to form a stabilized immunostimulatory complex, as discussed supra, ‘101 teaches that the tau immunogen fusion protein can be administered in combination with an adjuvant. Adjuvants are substances that do not themselves cause adaptive immune responses, but amplify or modulate the response to an accompanying antigen (See ‘101, col. 66, last paragraph to col. 67, 1st paragraph). ‘101 also teaches that ad adjuvant can be administered with an immunogen as a single composition (See ‘101, col. 67, last paragraph) thereby constituting where the two would be mixed. Alternatively, ‘101 teaches that the immunogen and adjuvant can be packaged and supplied in the same vial or can be packaged in separate vials and mixed before use (See ‘101, col. 67, last paragraph).
However, neither ‘101 or ‘909 teach where the adjuvant is CpG ODN.
Bode et al. teaches that synthetic ODNs containing unmethylated CpG motifs trigger cells that express Toll-like receptor 9 (including human plasmacytoid dendritic cells and B cells) to mount an innate immune response characterized by the production of Th1 and proinflammatory cytokines (See Bode, abstract). When used as vaccine adjuvants, CpG ODNs improve the function of professional antigen-presenting cells and boost the generation of humoral and cellular vaccine-specific immune responses (See Bode, abstract). These effects are optimized by maintaining ODNs and vaccine in close proximity (See Bode, abstract). Thus, Bode et al. demonstrates that CpG ODNs are well known to be used as an adjuvant to improve the inducement of a vaccine’s immune response, specifically when in close proximity (note: mixed with a vaccine would be considered in close proximity).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of ‘101 and substitute a CpG ODN as the adjuvant mixed with the tau immunogenic fusion protein in a pharmaceutical composition where the inclusion of a CpG ODN triggers cells that express Toll-like receptor 9 (including human plasmacytoid dendritic cells and B cells) to mount an innate immune response characterized by the production of Th1 and proinflammatory cytokines and improves the function of professional antigen-presenting cells and boost the generation of humoral and cellular vaccine-specific immune responses, especially when ODNs and vaccine are in close proximity. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because CpG ODNs were known to trigger cells that express Toll-like receptor 9 (including human plasmacytoid dendritic cells and B cells) to mount an innate immune response characterized by the production of Th1 and proinflammatory cytokines and to improve the function of professional antigen-presenting cells and boost the generation of humoral and cellular vaccine-specific immune responses, especially when ODNs and vaccine are in close proximity as taught by Bode et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the tau immunogen construct of ‘101 was a component in a pharmaceutical composition also containing an adjuvant that amplifies or modulates the response to an accompanying antigen. Therefore, substituting a CpG ODN as the adjuvant mixed with the tau immunogenic fusion protein in a pharmaceutical composition would support triggering cells that express Toll-like receptor 9 (including human plasmacytoid dendritic cells and B cells) to mount an innate immune response characterized by the production of Th1 and proinflammatory cytokines and improving the function of professional antigen-presenting cells and boost the generation of humoral and cellular vaccine-specific immune responses, especially when ODNs and vaccine are in close proximity by constituting the simple substitution of one known element for another to obtain predictable results and/or the use of known technique to improve similar devices (methods, or products) in the same way and/or the application of a known technique to a known device (method, or product) ready for improvement to yield predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
With respect to where the construct and CpG ODN are mixed to form a stabilized immunostimulatory complex, although ‘101 teaches that the construct and adjuvant are mixed, none of the cited references expressly teach that a stabilized immunostimulatory complex is formed when the two components are mixed. However, mixing the construct and an adjuvant such as a CpG ODN to form a stabilized immunostimulatory complex constitutes the intended use of the mixed combination of the construct and CpG ODN. Pursuant to MPEP 2111.04(I), [c]laim 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. However, examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are:
(A) "adapted to" or "adapted for" clauses;
(B) "wherein" clauses; and
(C) "whereby" clauses.
The court has found that the determination of whether clauses such as “wherein” and “whereby" is a limitation in a claim is dependent on the specific facts of the case. If the “wherein" or “whereby” clause limits a process claim where the clause gives meaning and purpose to the manipulative steps, it should be given patentable weight. Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002). However, the court also found (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” In the instant case, since the combination of cited references render obvious mixing the tau immunogen construct and an adjuvant where the adjuvant can be CpG ODN, and there are no specific mixing parameters claimed necessary to form a stabilized immunostimulatory complex, e.g., concentration of components, pH, etc., the cited references would necessarily suggest forming a stabilized immunostimulatory complex by virtue of mixing the construct and CpG ODN together.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 18-19, 22, 24, 27-28, and 30-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11,773,148 B2 (cited in the IDS received on 8/5/24). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘148 claims:
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(See ‘148, claims 1, 3, 5, 8-13 thereby corresponding to issued claims 1, 3, 6-9, 4-5, and 10, respectively). It is noted that the tau fragment of ‘148 contains instant SEQ ID NO: 115 (note: the ‘148 tau fragment is 100% identical to instant SEQ ID NO: 19). Moreover, it is noted that the tau peptide immunogen construct of ‘148 (i.e., SEQ ID NO: 69) is 100% identical to instant SEQ ID NO: 136 as recited in instant claim 32. Thus, the ‘148 claimed invention anticipates instant claims 18-19, 22, 24, 27-28, and 30-35. Therefore, the ‘148 claimed invention is not patentably distinct from the instantly claimed invention.
Allowable Subject Matter
Claims 21, 26, and 29 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. It is noted that there is no teaching or suggestion in the art to utilize a tau fragment that is limited to instant SEQ ID NO: 115.
Additionally, notwithstanding the 112(b) and obviousness-type double patenting rejections supra, the scope of claims 32 and 35 are free of the prior art. In particular, there is no teaching or suggestion in the art to utilize the specific tau fragments claimed in each of the recited sequences. The closest prior art for claims 21, 26, 29, 32, and 35 is Novak et al. US Patent No. 9,518,101 B2 issued on December 13, 2016, which teaches tau peptide immunogen constructs where the tau peptide is a fragment that includes instant SEQ ID NO: 115 (See 103 rejection supra for further details). ‘101 teaches 30-mer tau fragments that are immunogenic (See ‘101 Table 1) and additional fragments including VQIINKKLDLSNVQSKCGSKDNIKHVPGGG (SEQ ID NO: 4), HVPGGG (SEQ ID NO: 154) and KDNIKHVPGGGS (SEQ ID NO: 108) (See ‘101, col. 61, 1st to col. 62, 1st paragraph). However, ‘101 does not teach or suggest utilizing the specifically claimed tau fragments of instant SEQ ID NO: 115 and those in SEQ ID NOs: 131, 136, 140-141, and 144. Thus, the scope of claims 21, 26, 29, 32, and 35 is free of the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THEA D' AMBROSIO whose telephone number is (571)270-1216. The examiner can normally be reached M-F 11:00 to 8:00 pm.
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
