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 .
Election/Restrictions
Applicants’ election of Species A (i.e., Single and specific chain trimer (SCT) including indication of: 1. Single and specific first linker, indicating single and specific percent homology to a single and specific sequence identification number, Applicants’ election: GCGGSGGGGSGGGGS (SEQ ID NO: 1); 2. Single and specific amino acid substitution present in the major histocompatibility complex (MHC) I alpha chain, Applicants’ election: {Y84C}; and 3. Single and specific leader peptide, indicating single and specific percent homology to a single and specific sequence identification number, Applicants’ election: SUC2 (SEQ ID NO: 19)), in the reply filed on 10/09/2025 is acknowledged.
During a telephonic communication on 11/06/2025with Applicants’ representative (i.e., Adam Schoen), the percent homology/identity of the elected sequences was confirmed. Applicants election of a first linker that is at least about 90% homologous to SEQ ID NO: 1, as well as a leader peptide that shares 95% or greater sequence identity with SEQ ID NO:19, is acknowledged.
Claims 5-8,11 and 16-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Because Applicants did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon searching the elected species (i.e., Single and specific leader peptide, indicating single and specific percent homology to a single and specific sequence identification number, Applicants’ election: SUC2 (SEQ ID NO: 19)), additional species were found, e.g., PH05. Accordingly, for purposes of compact prosecution, the election of species is modified only to the extent of examining this additional species. Otherwise the election of species requirement is still retained.
Priority
The present application claims the benefit under 35 U.S.C 119 (e) to U.S. Provisional Application No. 62/980,088 filed 02/21/2020; and claims status as a 371 (National Stage) of PCT/US2021/018949 02/21/2021.
Claim Status
Claims 1-51 were originally filed and amended on 08/19/2022.
The amendment cancelled claims 25-51, and amended claims 3-9, 12-14, 16, 18-19 and 21-24.
Claims 1-4, 9-10, 12-15 and 18-24 are under consideration.
Information Disclosure Statement
The IDSs filed on 01/12/2023 and 05/31/2024 have been considered by the Examiner.
Claim Interpretation/Sequence Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 1, regarding the scope of “portion”, it is noted that the instant specification does not define what constitutes “a portion”. Rather the instant specification teaches that a “functional portion” or a “functional fragment” refers to a polypeptide or polynucleotide that comprises only a domain, motif, portion, or fragment of a parent or reference compound and the polypeptide or encoded polypeptide retains at least 50% activity associated with the domain, portion, or fragment of the parent or reference compound (see instant specification, pg. 19, lines 19-22). As such, the Examiner is interpreting the phrase “at least a portion…” as a functional portion of a parent reference compound that retains at least 50% activity.
For claim 3, regarding the scope of “homologous”, it is noted that the instant specification defines “homologous/homology and percent homology” as a nucleic acid sequence relative to a reference sequence (see instant specification, pg. 19, lines 3-5). The specification also recites that homologous sequences described include sequences having the same percentage identity as the indicated percentage homology (see instant specification, pg. 19, lines 8-10). However, a professor at Stanford University stated that the difference between homology, similarity and identity depends on the context; “homology” means that the sequences are evolutionarily related, “identity” is the fraction of amino acids that are the same between a pair of sequences after an alignment of the sequences (which can be done using only sequence information or structural information or some other information, but usually it is based on sequence information alone), and “similarity” is the score assigned based on an alignment using some similarity matrix (see Samudrala, R., “Difference Between Homology, Identity, and Similarity,” available online at http://www.bio.net/mm/proteins/1998-July/006538.html, pg. 1, 1st and 2nd paragraphs, accessed on 11/18/2025). In the instant case, the Examiner is interpreting the scope of the term “homology” as being the same as “sequence identity”. Therefore, since SEQ ID NO: 1 is 15 amino acids in length; a sequence that is at least about 90% identical would encompass up to 1 modification including any substitution, insertion, deletion, etc.
For claim 21, the Examiner is interpreting the scope of the leader peptide as sharing 95% or greater percent identity to SEQ ID NO: 19. Since SEQ ID NO: 19 is nineteen amino acids in length; a sequence that shares 95% or greater percent identity would encompass at least 1 modification including any substitution, insertion, deletion, etc.
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.
1. Claims 1-4, 9-10, 12-15 and 18-24 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. The preamble of independent claim 1 recites “a single chain timer (SCT) polypeptide comprising or consisting essentially of …” MPEP 2111.03 (III) states that [f]or the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising.”. Therefore, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the claimed invention because the difference between comprising and consisting essentially of has not been clearly stablished.. Since the transitional phrases overlap and make the preamble ambiguous and/or redundant; for purposes of searching for and applying prior art, the Examiner is interpreting the scope of the claim as comprising a target peptide, a first linker, at least a portion of a ß-2 microglobulin domain, a second linker and at least a portion of a MHC I α chain; or a pharmaceutically acceptable derivative thereof.
2. Claim 10 is 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 10 recites that the amino acid substitution is {Y84C}. Claim 10 depends from claim 9, which recites that at least a portion of the MHC I α chain comprises an amino acid substitution compared to a wild-type MHC I α chain. However, it has not been clearly stablished which portion of the MHC I α chain comprises a Tyrosine at position 84, nor whether position 84 is relative to the entire wild-type MHC I alpha chain or to a specific portion of the wild-type MHC I alpha chain. Additionally, the use of curly brackets (i.e., { }) is not routine and conventional nomenclature for indicating an amino acid substitution; instead amino acids enclosed by curly brackets denote any amino acid except for those in the string. Therefore an ordinary skilled artisan would not be able to ascertain the metes and bounds of the claim limitations recited in claim 10 because it unclear to which portion of the MHC I α chain is the substitution relative to, and it is also unclear whether tyrosine is substituted for cytosine at position 84, or whether the substitution at position 84 is any amino acid except for tyrosine and cytosine. In order to advanced prosecution, the Examiner is interpreting {T84C} as the substitution of tyrosine for cytosine at position 84 relative to the wild-type MHC I α chain.
3. Claim 13 is 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. In the instant case, claim 13 further narrows claim 1 and recites that the first linker has an amino acid substitution {G2C}. As discussed in the previous rejection, the use of curly brackets (i.e., { }) is not routine and conventional nomenclature for indicating an amino acid substitution; instead amino acids enclosed by curly brackets denote any amino acid except for those in the string. Therefore, it is not clear whether the content of the curly brackets indicates a substitution at the second position in the first linker, or whether any amino acid except Gly and Cys is present at the second position in the first linker, or whether there are two Glycines for one Cysteine present in the linker, or whether the first linker is required to have a cysteine present before a substitution takes place. In order to advance prosecution, the Examiner is interpreting claim 13 as an amino acid substitution of Gly for Cys at position 2 of the first linker.
4. Claims 14-15 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 14 further narrows, claim 1. Claim 1 recites that the SCT polypeptide comprises at least a portion of the MHC I α chain. However, claim 14 recites that a disulfide bridge forms between the first linker and the MHC I α chain. Therefore, an ordinary skilled artisan would not be able to ascertain the metes and bounds of the claimed invention with respect to the formation of the disulfide bridge between the first linker and the MHC I alpha chain. It has not been clearly stablished if the disulfide bridge forms between the first linker and at least a portion of the MHC I α chain or whether the bridge forms between the first linker and the entire the MHC I alpha chain.
5. Claim 15 is 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 15 depends upon claim 14, which also depends from claim 1. The claim limitations recited in parent claim 1 are drawn to a SCT polypeptide comprising a first linker, and at least a portion of the MHC I α chain. Parent claim 1 does not recite additional limitations regarding the first linker nor the portion of the MHC I α chain. Claim 15 recites the limitations "(i) the {G2C} of the first linker, or the second amino acid counted from the N-terminus of the first linker, wherein the second amino acid is C; and (ii) the {Y84C} of the MHC I alpha chain" in lines 1-3. There is insufficient antecedent basis for these limitations in the claim, because parent claim 1 does not recite any additional requirements/limitations with respect to the first linker and the portion of the MHC I α chain.
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.
6. Claims 1-2, 9-10, 12-15 and 18-21 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.
Independent claim 1 is drawn to a single chain trimer (SCT) polypeptide comprising or consisting essentially of a target peptide, a first linker, at least a portion of a beta-2 microglobulin domain, a second linker, and at least a portion of a major histocompatibility complex (MHC) I alpha chain. As discussed in the 35 U.S.C 112(b) above , the Examiner is interpreting the scope of the SCT polypeptide as comprising of a target peptide, a first linker, at least a portion of a ß-2 microglobulin domain, a second linker, and at least a portion of a MHC 1 α chain. In other words, the scope of the claimed polypeptide encompasses any amino acid sequence that encodes any target peptide, any first linker, any portion of a ß-2 microglobulin domain, any second linker, and any portion of a MHC 1 α chain and still exhibits the function of single chain trimer. As such, scope of claim 1 and dependent claims 2, 9-10, 12-15 and 18-21 encompass a vast array of sequences without a necessary core structure and/or sequence that would be needed for a polypeptide to exhibit the function of single chain trimer.
Applicants reduced to practice SEQ ID NOs: 5-9 which are depicted in Figs. 2A-2B, 3, 7, and 8. The amino acid sequences depicted in the figures are annotated and the position and/or arrangement of the comprising elements/portions and/or fragments that make up the claimed SCT polypeptide can be visualized. Additionally, the specification teaches that the peptide-Major Histocompatibility Complex (pMHC) can be constructed as a single chain trimer (SCT) with the general structure of P-L1-B-L2-A, where L1 and L2 are flexible linkers, P is a peptide ligand, A is a soluble form of the α chain MHC 1 and B is α-2 microglobulin (see specification, pg. 2, lines 9-11). It is noted that the sequences reduced to practice follow the general structure, except for SEQ ID NOs: 8-9 which do not include linker 1 (see instant specification, pg. 1, Table 1, and Figs. 7 and 8). It is also noted that the peptide ligand is represented by NYESO1 and the ß-2 microglobulin portion. The specification teaches that the target peptide is NY-ESO-1 (see pg. 24, line 9), it is also observed that the same target peptide (i.e., NY-ESO-1) is present at the N-terminus of the sequences reduced to practice. The sequences also depict the claimed portion of the ß-2 microglobulin domain and the claimed portion of the MHC I alpha chain; however the specification is void of details pertaining to the claimed portions (i.e., sequence length, percent identity and starting and/or ending amino acid positions relative to a parent sequence). With respect to the second linker, it is also noticed that the second linker is a flexible Gly-Ser linker positioned between the two portions of the claimed ß-3 microglobulin domain and the MHC-I α chain.
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. MPEP 2163 (I)(A). The sequences reduced to practice (i.e., sequences listed in Table 1) do not share a common core structure; without an indication of a core structure, sequence or residues that would be necessary in order for a sequence exhibit the claimed function (i.e., single chain trimer), it would be difficult for a skilled artisan to envision the correlation between structure and function for the whole genus and/or to predict what would be covered by the functionally claimed genus because Applicants have failed to provide a representative number of species to support the scope of the whole genus.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, US2010/0159594 A1 teaches single chain trimer (SCT) molecules comprising an MHC antigen peptide sequence, a ß-2-microglobulin sequence and a full-length MHC class I heavy chain sequence joined by linker sequences (see US2010/0159594 A1, cited in the IDS filed on 05/31/2024, herein after “Hansen” at Abstract). Hansen teaches Table 5, which depicts single chain constructs and sequences of some peptide antigens (i.e., target peptide) and some linkers (see pg. 11, para[0101] and Table 5). Hansen also discloses the sequence identification numbers that represent the ß2-microblogulin sequence (i.e., SEQ ID NO: 6) and the MHC class I heavy chain sequence (i.e., SEQ ID NO: 7) (see pg. 2, para[0017-0018]). Alternatively, Hansen also teaches that the MHC class I heavy chain sequence can also be represented by SEQ ID NO: 8 or by SEQ ID NO: 9 which comprises a substitution at position 84 (see pg. 2, para[0019]).
Similarly, WO2019195310(A1) describes antigenic peptide MHC molecules (see WO2019195310(A1) cited in the IDS filed on 05/31/2024, herein after “Bethune” at abstract). Bethune’s invention incorporates a first universal target sequence comprising the sequence shown in SEQ ID NO: 3, the ß2M sequence comprising the sequence shown in SEQ ID NO: 106, the MHC allele sequence comprising a sequence selected from the group consisting of sequences shown in SEQ ID NOs: 109-174 (see pg. 3, para[0007]). Therefore, Hansen’s and Bethune’s teachings present compelling evidence stablishing the functional identities of a target peptide, a portion of a ß2 microglobulin domain, and a MHC I alpha chain that are predominantly incorporated in single chain trimer polypeptides. Thus, claims 1-2, 9-10, 12-15 and 18-21 are directed to a sequence with a certain function but no correlated structure associated with that function. Without such structure, the specification does not convey possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by providing a representative number of species of the genus. In the instant case, Table 1 in the specification teaches the sequence identification numbers reduced to practice, in particular SEQ ID NOs: 5-9 which represent SCT polypeptide (see pg. 1, and Figs. 2A-2B, 3 and 7-8). Thus, evidence of four SCT polypeptides, is not sufficient for the skilled artisan to envisage what constitutes a necessary core structure and/or sequence that would preserve function.
Therefore, claims 1-2, 9-10, 12-15 and 18-21 do not meet the written description requirement. Please note that claims 3-4 and 21-23 are not part of this rejection, because the claims recite a necessary core structure and/or sequence that exhibit the function of first linker (i.e., SEQ ID NO:1) and leader peptide (i.e., SEQ ID NO: 19).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
7. Claims 1-2 and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2010/0159594 A1 Pub. Date: Jun. 24, 2010, cited in the IDS filed on 05/31/2024 (here in after “Hansen”).
For claim 1, Hansen discloses single chain trimer (SCT) molecules, comprising an MHC antigen peptide sequence, a ß2-microglobulin sequence and a full-length MHC class I heavy chain sequence, joined by linker sequences (see Abstract). Since Hansen’s SCT molecules comprise a full-length MHC class I heavy chain sequence, it must follow that the full-length MHC class I heavy chain includes at least a portion of the MHC I α chain. Hansen illustrates the structure of the single chain trimers in Fig. 6, where it can be perceived that the peptide sequence could be any antigenic peptide, thereby corresponding to the instantly claimed target peptide as recited in instant claim 1; and where the MHC class I heavy chain could be HLA-A or HLA-B (see Fig. 6). Hansen also discloses that the ß2-microglobulin sequence comprised by the SCT molecules can be a full-length ß2-microglobulin as expressed on the cell surface (i.e., without the leader peptide sequence) (see pg. 2, para[0017]); thereby it must follow that the full-length ß2-microglobulin includes at least a portion of a ß2-microglobulin domain. As such Hansen’s SCT molecule anticipate to the instantly claimed SCT polypeptide as recited in claim 1.
For claim 2, Hansen discloses that the peptide linkers can predominantly comprise amino acids with small side chains such as glycine, alanine and serine (see pg. 6 para[0054]), thereby corresponding to wherein the first linker is a peptide as recited in instant claim 2. As such, Hansen’s disclosure anticipates the claim limitations recited in instant claim 2.
For claim 9, Hansen discloses Fig. 6, which depicts the SCT structure where the HLA class I heavy chain could be HLA-A or HLA-B and comprises a mutation at Y84 (see Fig. 6). As such, Hansen’s Fig. 6 anticipates the claim limitations as recited in instant claim 9.
Accordingly, claims 1-2 and 9 are anticipated by Hansen’s disclosure.
3. Claims 1-2, 9-10, 12-15 and 18-20 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by WO 2019/195310 A1 International Pub. Date: Oct. 10, 2019, cited in the IDS filed on 05/31/2024 (here in after “Bethune”).
For claim 1, Bethune discloses antigenic peptide-MHC molecules, termed comPACTs (see Abstract). In particular, Bethune’s Fig. 1 depicts the design of an exemplary comPACT mini-gene, where SS refers to the optional signal sequence; US 1 refers to the first universal target site; neoantigen refers to the antigenic peptide sequence site; US2 refers to the second universal target site; L1 refers to the optional first linker sequence; ß2M refers to the ß-2-microglobulin domain sequence; L2 refers to the optional second linker sequence; MHC heavy chain refers to the MHC heavy chain allele (see pg. 15, para[0066] and Fig. 1). Bethune also discloses that the comPACTs refer to a single polypeptide fusion
Including a MHC class I heavy chain comprising, e.g., the α1, α2, and α3 domains that forms an MHC display moiety (see pg. 21, para[00112]). As such Bethune’s disclosure anticipates the claimed SCT polypeptide, wherein the antigenic peptide sequence site corresponds the instantly claimed target peptide, the L1 first linker sequence corresponds to the instantly claimed first linker, the ß-2-microglobulin domain sequence corresponds to at least a portion of a ß2-microglobulin domain as recited in instant claim 1, the L2 second linker sequence corresponds to the instantly claimed second linker, and the MHC heavy chain refers to the MHC heavy chain allele corresponds to the instantly claimed portion of a MHC I α chain as recited in instant claim 1. For claim 2, Bethune’s claim 42 recites that the second universal target sequence further comprises a first linker sequence (see pg. 83, claim 42). Such linker sequences include, but are not limited to, glycine-serine sequences comprising one or more repeating units of a GS, SG, GGGGS (G4S), GGGS (G3S), GSGGS, or GCGGS sequence motifs (see pg. 26, para[00128]).
For claims 9-10, Bethune’s Example 1 discloses that the MHC allele may also be modified or mutated (e.g., Y84A or Y84C) to improve folding or increase binding of the antigenic peptide with MHC protein (see pg. 45, para[00190]).
For claims 12-14, Bethune’s Fig. 11 depicts the construct where L1 could be GSGGS or GCGGS. Figure 11 also illustrates that a disulfide trap forms between L1 and MHC heavy chain (see Fig. 11).
For claim 15, Bethune discloses that linkers can also comprise cysteine residues for disulfide bonds between the linker sequence and the MHC allele sequence, such that the cysteine residues form a disulfide trap (see pg. 27, para[00129]). The linker sequence or second universal target peptide comprises a cysteine residue that forms a disulfide bond with the MHC allele (see pg. 27, para[00129]).
For claim 18, Bethune’s shows the comPACT construct where after the MHC heavy chain, there is a third linker (see Fig. 1), followed by a purification cluster (i.e., a tag) and a BGH polyA sequence (see Fig. 6).
For claims 19-20, Bethune disclose Table 3, which lists exemplary signal sequences (see pg. 27). Additionally, Bethune discloses that that the signal sequence can be a secretion signal sequence and that secretion signal sequences direct translated proteins in mammalian cells through the secretory pathway, and ensure that the translated proteins are subject to cellular quality control (see pg. 27. Para[00130]).
As such, the disclosure of Bethune anticipates the claim limitations recited in instant claims 1-2, 9-10, 12-15 and 18-20.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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).
4. Claims 1 and 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/195310 A1 International Pub. Date: Oct. 10, 2019 (here in after “Bethune”) as applied to claim 1 above, and further in view of US2015/0344586 Pub. Date: Dec. 3, 2015 (herein after “Georges”) as applied to claims 3-4 herewith.
Regarding claim 1, please see discussion of Bethune above.
Regarding claims 3-4, as previously discussed, Bethune’s Fig. 11 shows where the first linker is GSGGS or GCGGS (see Fig. 11). Bethune also teaches that any appropriate flexible linker sequence known in the art may be used (see pg. 26, para[00128]). Such linker sequences include, but are not limited to, glycine-serine sequences comprising one or more repeating units of a GS, SG, GGGGS (G4S), GGGS (G3S), GSGGS, or GCGGS sequence motifs (see pg. 26, para[00128]). Additionally, Bethune teaches that linkers can also comprise cysteine residues for disulfide bonds between the linker sequence and the MHC allele sequence, such that the cysteine residues form a disulfide trap (see pg. 27, para[00129]). However, Bethune does not expressly teach wherein the first linker has an amino acid sequence that is at least about 90% homologous to GCGGSGGGGSGGGGS (SEQ ID NO: 1), as recited in instant claim 3; nor wherein the first linker has an amino acid sequence that is GCGGSGGGGSGGGGS (SEQ ID NO: 1), as recited in instant claim 4.
Georges teaches a disulfide-linked multivalent multi-function protein comprising an antibody fragment and one, two or more disulfide-linked MHC class I components (see pg. 1, para[0003]).
Georges adds that the virus-derived peptide is fused to the ß-2 microglobulin via a first linker peptide (see pg. 4, para[0089]); and that in one embodiment the first linker peptide has the amino acid sequence of SEQ ID NO: 139 (see pg. 5, para[0115]). Georges’ SEQ ID NO: 139 consists of GCGGSGGGGSGGGGS (see pg. 5, para[00940]). Additionally, George’s SEQ ID NO: 139 is 100% identical to instant SEQ ID NO: 1.
Furthermore, Georges teaches that the linker has the function to ensure that polypeptides conjugated to each other can perform their biological activity by allowing the polypeptides to fold correctly and to be presented properly (see pg. 19, para[0451]). The peptide linker is rich in glycine, glutamine, and/or serine residues; and these residues are arranged e.g. in small repetitive units of up to five amino acids(see pg. 19, para[0451]). Additionally disulfide-linked multivalent multi-function proteins as reported by Georges, comprising one antigen presenting domain can be produced with improved yields and have an improve thermal stability (see pg. 20, para[0464]). Further without being bound by this theory disulfide-linked multivalent multifunction proteins comprising one antigen presenting domain are more specific with respect to T-cell activation (see pg. 20, para[0464]).
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to modify the teachings of Bethune, by incorporating the teachings of Georges in order to arrive at the claimed SCT polypeptide wherein the first linker has an amino acid sequence that is about 90% identical to SEQ ID NO: 1. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because the linker has the function to ensure that polypeptides conjugated to each other can perform their biological activity by allowing the polypeptides to fold correctly and to be presented properly. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that Bethune’s first linker can also comprise cysteine residues for disulfide bonds to form between the linker sequence and the MHC allele sequence, thereby forming a disulfide trap. An ordinary skilled artisan would also have been motivated with reasonable expectation of success given that disulfide-linked multivalent multi-function proteins comprising one antigen presenting domain can be produced with improved yields and have an improve thermal stability and are more specific with respect to T-cell activation as taught by Georges. Therefore, substituting Bethune’s first linker for George’s first linker (i.e., SEQ ID NO: 139) would support antigenic peptide-MHC molecules (i.e., comPACTs) by constituting a simple substitution of one known element for another to obtain predictable results and/or use of known technique to improve similar devices (methods, or products) in the same way 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.
5. Claims 1 and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/195310 A1 International Pub. Date: Oct. 10, 2019 (here in after “Bethune”) as applied to claim 1 above, and further in view of US2018/0037898 A1 Pub. Date: Feb. 8, 2018 (herein after “Ring”) as applied to claims 21-24 herewith.
Regarding claim 1, please see 35 U.S.C 102 discussion of Bethune above.
Regarding claims 21-23, Bethune teaches that the comPACT polynucleotide and polypeptide may comprise a signal sequence, e.g., encoding a signal peptide in the case of a polynucleotide (see pg. 27, para[00130]). The signal sequence can be a secretion signal sequence; secretion signal sequences direct translated proteins in mammalian cells through the secretory pathway, and ensure that the translated proteins are subject to cellular quality control (see pg. 27, para[00130]). Inclusion of secretory signals can ensure that the comPACT proteins are secreted into the cellular media, such that they are homogenously well-folded and more easily isolated from the media or clarified supernatant (see pg. 27, para[00130]). Please note that the instant specification at pg. 22, lines 14-15 recites that the term “leader sequence” is used interchangeably with “signal sequence” and also referred to as “leader peptide”.
However, Bethune does not expressly teach wherein the leader peptide shares 95% or greater sequence identity with a sequence of SUC2 (SEQ ID NO: 19), as recited in instant claim 21.
Ring teaches methods and compositions for displaying a protein of interest (POI) on the surface of a eukaryotic cell by fusing the POI to a signal polypeptide, a stalk polypeptide, and a surface anchor polypeptide to generate a surface accessible fusion protein (see Abstract). Ring teaches that if a surface accessible fusion protein will be expressed in a yeast cell, the signal polypeptide can be from a yeast protein (e.g., in some cases from the same species of yeast) (see pg. 5, para[0041]). Ring’s examples of suitable signal polypeptides include but are not limited to those from (or derived from) the following yeast proteins: mating factor alpha, Aga2p, Pho5p, and Suc2p (see pg. 5, para[0041]). Ring also teaches MLLQAFLFLLAGFAAKISAS as SEQ ID NO: 15 which represents signal polypeptide from SUC2p; which is 100% identical to instant SEQ ID NO: 19.
Regarding claim 21, Ring teaches that expression of proteins on the surface of eukaryotic cells (e.g., yeast cells), a technique known as surface display, can be used for a diverse array of purposes (see pg. 1, para[0002]). For example, because yeast are eukaryotic, using yeast for surface display is well suited for engineering and modifying mammalian proteins (e.g., via directed evolution) that require posttranslational modifications for efficient folding and activity (e.g., cell-surface and secreted proteins such as antibodies, receptors, cytokines, and the like) (see pg. 1, para[0002]). In one example of surface display, a protein of interest is fused to the Aga2p protein, which is naturally used by yeast to mediate cell-cell contacts during mating (see pg. 1, para[0002]).
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to modify the teachings of Bethune, and incorporate the teachings of Ring in order to arrive at the claimed SCT polypeptide wherein the leader peptide shares 95% or greater sequence identity with SEQ ID NO: 19, and wherein the tether peptide is Aga2. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because methods and compositions for displaying a protein of interest (POI) on the surface of a eukaryotic cell by fusing the POI to a signal polypeptide were well-known; and because using yeast for surface display is well suited for engineering and modifying mammalian proteins (e.g., via directed evolution) that require posttranslational modifications for efficient folding and activity (e.g., cell-surface and secreted proteins such as antibodies, receptors, cytokines, and the like). One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that Bethune’s comPACT polypeptide comprises a signal sequence that directs translated proteins in mammalian cells through the secretory pathway and ensure that the translated proteins are subject to cellular quality control. An ordinary skilled artisan would also have been motivated with reasonable expectation of success given that Rings’ signal polypeptides include but are not limited to those from (or derived from) the following yeast proteins: mating factor alpha, Aga2p, Pho5p, and Suc2p; and given that Ring’s Suc2p (i.e., SEQ ID NO: 15) is 100% identical to instant SEQ ID NO: 19. Therefore, Ring’s signal peptides (i.e., SEQ ID NO: 15 and Aga2p) would support the antigenic peptide-MHC molecules (i.e., comPACTs) by constituting 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.
In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 USC 103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references discussed above.
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.
6. Claims 1-4, 9, 12-14, 18-19, 20-21 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 9, 13-15, 19-22 and 25 of copending Application No. 18/685,109 in view of WO 2019/195310 A1 International Pub. Date: Oct. 10, 2019 (here in after “Bethune”).
Regarding instant claim 1, copending application No. 18/685,109 claims: A single chain trimer (S CT) polypeptide comprising or consisting essentially of a target peptide, a first linker, at least a portion of a beta-2 microglobulin domain, a second linker, and at least a portion of a human leukocyte antigen allele B*35 (HLA-B*35) alpha chain; or a pharmaceutically acceptable derivative thereof (see ‘109, claim 1).
Regarding instant claim 2, copending application No. 18/685,109 claims: The SCT polypeptide of claim 1, wherein the first linker is a peptide (see ‘109, claim 2).
Regarding instant claims 3-4, copending application No. 18/685,109 claims: The SCT polypeptide of claim 1, wherein the first linker has an amino acid sequence that is at least about 90% homologous to GCGGSGGGGSGGGGS (SEQ ID NO: 1) (see ‘109, claim 3).
Regarding instant claim 9, copending application No. 18/685,109 claims: The SCT polypeptide of claim 1, wherein the at least a portion of the HLA-B*35 alpha chain comprises one or more amino acid substitutions compared to a wild-type HLA-B*35 alpha chain (see ‘109, claim 9).
Regarding instant claim 12, copending application No. 18/685,109 claims: The SCT polypeptide of claim 9, wherein the second amino acid counted from the N-terminus of the first linker is C (see ‘109, claim 13).
Regarding instant claim 13, copending application No. 18/685,109 claims: The SCT polypeptide of claim 9, wherein the first linker has an amino acid substitution {G2C} (see ‘109, claim 14).
Regarding instant claim 14, copending application No. 18/685,109 claims: The SCT polypeptide of claim 9, wherein a disulfide bridge forms between the first linker and the HLA-B*35 alpha chain (see ‘109, claim 15).
Regarding instant claim 18, copending application No. 18/685,109 claims: The SCT polypeptide of claim 1, further comprising a tag, a third linker, and/or a tether peptide (see ‘109, claim 19).
Regarding instant claim 19, copending application No. 18/685,109 claims: The SCT polypeptide of claim 19, further comprising a leader peptide (see ‘109, claim 20).
Regarding instant claim 20, copending application No. 18/685,109 claims: The SCT polypeptide of claim 20, wherein the leader peptide directs the SCT polypeptide to the ER, facilitates ER to Golgi transport, and/or facilitates aspects of late secretory processing (see ‘109, claim 21).
Regarding instant claims 21-23, copending application No. 18/685,109 claims: The SCT polypeptide of claim 21, wherein the leader peptide shares 95% or greater sequence identity with a sequence of SUC2 (SEQ ID NO: 19) (see ‘109, claim 22).
Regarding instant claim 24, copending application No. 18/685,109 claims: The SCT polypeptide of claim 19, wherein the tether peptide is Aga2 (see ‘109, claim 25).
Bethune’s Fig. 1 depicts the design of an exemplary antigenic peptide-MHC molecules, termed comPACT, where SS refers to the optional signal sequence; US 1 refers to the first universal target site; neoantigen refers to the antigenic peptide sequence site; US2 refers to the second universal target site; L1 refers to the optional first linker sequence; ß2M refers to the ß-2-microglobulin domain sequence; L2 refers to the optional second linker sequence; MHC heavy chain refers to the MHC heavy chain allele (see pg. 15, para[0066] and Fig. 1).
Bethune also teaches that in some embodiments, the MHC allele is a class I HLA allele (see pg. 4, para[0010]); and that in other embodiments, the HLA allele comprises an HLA-A, HLA-B, or HLA-C allele (see pg. 4, para[0010]). Furthermore, that the HLA allele is selected from the group consisting of HLA-B*35:01 or HLA-B*35:03 (see pg. 4, para[0011]). Human leukocyte antigen (HLA) typing can be determined from a tumor or blood sample and the HLA information can be utilized together with identified putative neoantigen peptide sequences in a predictive algorithm for MHC binding (see pg. 38, para[00168]). HLAs commonly found in the human population, such as HLA-B*35, can also be included in neoantigen predic