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 .
DETAILED ACTION
1. Applicant’s amendment and response filed 8/4/25 is acknowledged and has been entered.
2. Applicant is reminded pf Applicant's election of Group I and species of: a first fusion polypeptide comprising in order from N-terminus to C-terminus, a cancer-associated T cell peptide epitope, a linker comprising glycine and serine, and a b2m polypeptide, and a second fusion polypeptide comprising, in order from N-terminus to C-terminus, at least one 4-1BBL polypeptide, an MHC class I heavy chain polypeptide and an Ig Fc polypeptide, wherein the first and second polypeptide are linked via a disulfide bond between a Cys in the b2m polypeptide and a Cys in the MHC class I heavy chain polypeptide in Applicant’s amendment and response filed 9/19/24 is acknowledged.
Applicant is reminded that Applicant subsequently elected in Applicant’s amendment and response filed 12/27/24 the following species election in response to the communication mailed 11/1/24 stating that no claims read upon the species elected (in the said amendment and response filed 9/19/24). Applicant had subsequently elected the following species:
A heterodimer comprising:
a) a first fusion polypeptide comprising, in order from N-terminus to C-terminus, a pathogen-associated peptide epitope, a linker comprising glycine and serine, and a b2m polypeptide; and
b) a second fusion polypeptide comprising, in order from N-terminus to C-terminus, at least one 4-1BBL polypeptide, an MHC class I heavy chain polypeptide, and an Ig Fc polypeptide;
wherein the first and second peptide are linked via a disulfide bond between a Cys in the b2m polypeptide and a Cys in the MHC class I heavy chain polypeptide.
Claims 100 and 102-112 are presently being examined.
3. 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.
4. Claims 100 and 102-112 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. This is a written description rejection.
This is a new ground of rejection necessitated by Applicant’s amendment filed 8/4/25.
Applicant has broadly claimed a multimeric polypeptide comprising a heterodimeric polypeptide, wherein the heterodimeric polypeptide comprises:
a) a first polypeptide comprising, in order from N-terminus to C-terminus:
i) a pathogen-associated peptide epitope; and
ii) a b2m polypeptide; and
b) a second polypeptide comprising
i) an MHC class I heavy chain polypeptide;
ii) an Ig Fc polypeptide; and
iii) one to three 4-1BBL polypeptides, and including the limitations recited in the dependent claims.
As such, the multimeric polypeptide comprises any MHC class I heavy chain and b2m from the genus of all mammalian MHC class I molecule (instant specification at [0012]) and any pathogen-associated epitope in the universe of pathogen-associated epitopes, wherein the MHC class I and the pathogen associated epitope must possess the functional property of binding to each other (i.e., the pathogen-associated peptide in the peptide binding groove formed by the MHC class I heavy chain and b2m light chain), and when so bound, the complex thereof must possess the functional property of binding to a TCR on a T cell and with an affinity that is less than 10-6 M and of eliciting a T cell response (e.g., [00124]). (Applicant may potentially obviate this point of the rejection by amending the claims to recite an active method step for a process of making the polypeptide by providing the pathogen-associated peptide epitope.)
As such, the multimeric polypeptide must also comprise a 4-1BBL polypeptide, wherein the specification discloses that in some cases, a 4-1BBL polypeptide of the present disclosure comprises an amino acid sequence having at least 75% amino acid sequence identity to amino acids 50-254 of the 4-1BBL amino acid sequence depicted in Figure 27 (i.e., human 4-1BBL ectodomain which is SEQ ID NO: 96). However, this is not a limiting definition thereof. The specification also discloses that the immunomodulatory (“MOD”) polypeptide of the present disclosure (such as the 4-1BBL polypeptide) has the functional property of activating or inhibiting a target T cells (e.g., [00162], [0021], [0025]). The specification discloses at [00359] that the species shown in Figure 27 is a stimulatory MOD (also [00143]).
As such, as pertains to dependent claims 105, 106, 111 and 112, the multimeric polypeptide comprises a disulfide bond that links a cysteine in the first polypeptide to a cysteine in the second polypeptide (claims 105 and 111), wherein the disulfide bond links a cysteine in the b2m polypeptide to a cysteine in the MHC class I heavy chain polypeptide (claims 106 and 112). That is, the disulfide-bonded heterodimer must possess the functional property of binding to the peptide epitope and visa versa, with the disulfide bond not interfering with said functional property. The disulfide-bonded heterodimer having the recited disulfide bond comprises a peptide epitope (a peptide that must possess the functional property of binding in the cognate MHC class I peptide binding site (and visa versa, the cognate MHC class I must possess the functional property of binding the said peptide, which is dependent upon a correctly folded MHC class I heavy chain that associates with b2m, a correctly folded and configured peptide binding groove in which the disulfide bond does not interfere with peptide binding and presentation) and when so bound, possess the functional property of binding to a TCR on a T cell and eliciting a T cell response.
The specification does not disclose a representative number of species of such pathogen-associated epitopes, nor of 4-1BBL polypeptides, in the claimed composition, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.' " Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. 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. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." See MPEP 2163 II.3.
Although a number of pathogen-associated peptide epitopes for some MHC molecules are known in the art, it is clear that the breadth of the genus of such pathogen-associated epitopes and the cognate MHC molecule for each is much broader and structurally diverse. Evidentiary reference HLA Nomenclature (2023, 2 pages, of record) teaches that for human MHC class I molecules alone, there are over 25,000 different alleles. The breadth of the genus of pathogen associated epitopes is broad and structurally diverse, encompassing those from any protein from any pathogen in the universe of pathogens. The specification as noted above, discloses that the MHC class I may be any MHC class I molecule, human or other mammalian, and may also comprise an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 5 (the specification does not disclose what this sequence is in particular, but the Examiner presumes it may be a consensus sequence for one or more classical [human] HLA class I molecules) (e.g., [0035] at page 14).
Although the amino acid sequences of human and some other mammalian MHC are known in the art, the pathogen-associated epitopes to which they bind cannot be visualized a priori. This is because there is no structure function relationship between the primary amino acid sequence of a peptide and the MHC to which it binds, nor when bound which of the said peptides in complex with its cognate MHC possess the functional property of binding to a TCR and eliciting a T cell response. Factors come into play in vivo that have no relationship to the amino acid sequence of the pathogenic peptide that can influence whether or not a cognate T cell exists in the repertoire and if the binding of the peptide/MHC complex can activate a T cell (e.g., antigen processing, peptide transport, T cell repertoire, T cell precursor frequency, peptide hydrophobicity and stability) (see for example, Celis et al (Mol. Immunol., 1994, 31(18): 1423-1436, of record), Ochoa-Garay et al (Molec. Immunol., 1997, 34: 273-281, of record) and Karin et al (J. Exp. Med., 1994, 180: 2227-2237, of record)). Ochoa-Garay et al teach that the immunogenicity of a peptide (i.e., the ability to bind to and stimulate a T cell) cannot always be predicted from its affinity for MHC or the presence of MHC binding motifs, especially page 279, last sentence and continuing onto page 280).
As pertains to a lack of structure/function relationship for the peptide and the functional property of binding to a MHC class I molecule (the genus of which are highly polymorphic), the art recognizes that there is no structure/function relationship for a particular peptide to bind to a particular MHC class I molecule; although there are predictive algorithms that may be employed to predict peptides that can potentially bind to a particular MHC molecule, these algorithms yield false positive results, and each peptide must still be tested for binding. See for example evidentiary reference Weiczorek et al (Front. Immunol. 2017, article 292: 1-16, of record) that teaches that the groove in between the alpha 1 and alpha 2 domains helices of MHC class I molecules accommodates peptides based on the formation of a set of conserved hydrogen bonds between the side chains of the MHC molecule and the backbone of the peptide and the occupation of defined pockets by peptide side chain anchor residues. Wieczorek et al teach that the type of interactions of individual peptide side chains with the MHC depend upon the geometry, charge distribution and hydrophobicity of the peptide binding groove. Wieczorek et al teach that prediction of peptide binding based upon bioinformatics algorithms (i.e., in silico predictions) yield false positive results. (See entire reference, especially page 2 at column 1 and the para spanning columns 1-2). See also evidentiary reference Reche and Reinherz (G. Nicosia et al, Eds. ICARIS 2004, LNCS 3239: 189-1196, of record) that teaches that analysis indicates that the overlap between the peptide binding specificities of HLA class I molecules is mostly confined to alleles belonging to the same gene, but overlap exists between some alleles belong to the HLA-A and HLA-B genes. Reche and Reinherz teach that confirmation of the peptide binding specificities would need to be experimentally verified. Reche and Reinherz teach a prediction tool for prediction of promiscuous peptide binders to the supertypes, A2, A3, B7, B15 and A24. However, the results of any prediction tool must still be verified experimentally (see entire reference)
As is stated above in this rejection, there is no limiting definition for at least one 4-1BBL polypeptide, and as such, the said limitation is not limited to the human 4-1BBL ectodomain depicted in Figure 27, nor those having at least 75% amino acid sequence identity thereto (and the specification does not disclose which amino acid residues may be altered and to what other amino acid residues and/or that may be deleted and/or added). As is also stated above, the specification discloses that this said human 4-1BBL ectodomain has a stimulatory functional property; however, there is no requirement that the at least one 4-1BBL polypeptide be stimulatory, just immunomodulatory.
As pertains to the disulfide bond recited in the instant dependent claims 105, 106, 111 and 112, the specification discloses that the genus of MHC class I polypeptides encompasses any mammalian MHC [0012], including classical or non-classical MHC ([00272] describes some human MHC class I classical and non-classical MHC). The specification further discloses that this “disulfide lock” may occur between certain residues in HLA (human MHC class I) and b2m [00222]-[00251], [00138]. The specification discloses that SEQ ID NO: 4 and 5 represent b2m and HLA sequences referred to [00251]. As the breadth of the genus of MHC class I polypeptides is much broader than the examples disclosed in the specification, the specification is not clear as to what SEQ ID NO: 5 actually is (except presumably some HLA I sequence or consensus sequence), and the specification does not disclose a representative number of species for the recited genus, the specification does not provide adequate written description thereof.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the pathogen-associated epitope, the at least one 4-1BBL polypeptide, nor the disulfide locked heterodimer polypeptides of the multimeric polypeptide recited in the instant claims. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such multimeric polypeptides at the time the instant application was filed.
Applicant’s arguments are of record in the amendment and response filed 8/4/25 on pages 7-9.
Applicant’s arguments have been fully considered but are not persuasive.
Applicant argues that the individual components of the multimeric polypeptide were known by those of skill in the art prior at [to] the time of filing.
However, although the sequences of over 25,000 different human (HLA) MHC class I molecules and of some limited mammalian (e.g., mouse, rat) MHC class I molecules were known in the art before the time the invention was made, the amino acid sequences of different extremely structurally diverse pathogen-associated peptide epitopes from the genus of all pathogen proteins for each of the different over 25,000 different MHC class I molecules were not; they cannot be envisioned a priori, but must be determined by experimentation, as is enunciated in the instant rejection. This point also rebuts Applicant’s argument that the specification includes exemplary pathogen-associated peptide epitopes and such epitopes were well known to persons of ordinary skill prior to the filing date, and Applicant points to references that were not provided with Applicant’s said response. None-the-less, the instant specification discloses non-limiting lists of some pathogens from which epitopes may be discovered, but does not provide the primary amino acid sequences of epitopes that can bind a particular (over 25,000 different) MHC class I molecule, nor for the breadth of the genus of peptide epitopes from all pathogens for all MHC class I molecules. There is no evidence of record in the art for a representative number of such pathogen-associated peptide epitopes for the breadth of pathogen proteins and MHC class I molecules. Applicant’s arguments pertaining to numerous methods for identifying such epitopes are also not persuasive, as experimentation is not an adequate rationale for establishing sufficient written description.
The Examiner presented a suggestion to potentially obviate this portion of the rejection that pertains to the pathogen-associated MHC I epitope in the last office action, and it also appears above in the instant rejection.
With further regard to Applicant’s arguments that the stimulatory activity of 4-1BBL has been known prior to Applicant’s filing date (and again referencing an article that has not been provided with Applicant’s response) is not persuasive, as the claims do not recite 4-1BBL, but instead recite “4-1BBL polypeptides”. Applicant’s examples in the specification pointed to by Applicant pertain to a native 4-1BBL ectodomain. It is clear that the limitation “4-1BBL polypeptides” is vastly broader than a native 4-1BBL ectodomain. As is stated in the instant rejection:
“there is no limiting definition for at least one 4-1BBL polypeptide, and as such, the said limitation is not limited to the human 4-1BBL ectodomain depicted in Figure 27, nor those having at least 75% amino acid sequence identity thereto (and the specification does not disclose which amino acid residues may be altered and to what other amino acid residues and/or that may be deleted and/or added). As is also stated above, the specification discloses that this said human 4-1BBL ectodomain has a stimulatory functional property; however, there is no requirement that the at least one 4-1BBL polypeptide be stimulatory, just immunomodulatory.”
5. 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.
6. Claims 102-106 and 108-112 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.
This is a new ground of rejection necessitated by Applicant’s amendment filed 8/4/25.
Claims 102 and 108 recite the limitation “more than one 4-1BBL ectodomain polypeptide”. This limitation lacks antecedent basis in instant base claim 100 (which recites “one to three 4-1BBL polypeptides”).
7. For the purpose of prior art rejections, the filing date of the instant claims is deemed to be the filing date of PCT/US2015/035777, i.e., 6/15/2015, as provisional application 62/013,715 does not provide support for the full scope of the component portions and arrangements thereof of the multimeric polypeptide.
8. 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.
9. Claim interpretation: The claims recite the open transitional phrase “comprising” , opening the claim to encompass other non-recited elements or portions. The limitation “A multimeric polypeptide comprising a heterodimeric polypeptide,” wherein the heterodimeric polypeptide comprises” the recited first and second polypeptides (polypeptides being separate chains), the said limitation is being interpreted as being a heterodimer comprising a first polypeptide and a second polypeptide. (Note that the disclosure of the instant specification pertaining to disulfide-locked constructs consist of two separate polypeptide chains.)
10. The prior rejection of claims 100 and 102-112 as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31-49 of copending Application No. 17/342,518 is hereby withdrawn, as ‘518 is now abandoned.
11. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 17/959,065 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 100, 102-104 and 107-110 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 73-92 of 17/959,065 in view of Botten et al (J. Virol. 2006, 80(17): 8351-8361, of record).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 73-84 and 88-90 of 17/959,065 are drawn to a multimeric polypeptide/pharmaceutical composition thereof comprising a first polypeptide comprising an epitope and a b2m polypeptide and a second polypeptide comprising a MHC class I heavy chain polypeptide, an Ig Fc polypeptide and at least one immunomodulatory polypeptide that is a 4-1BBL polypeptide, with optional linkers between the components thereof.
Claims 85-87 of 17/959,065 are drawn to one or more nucleic acids individually or collectively encoding the first and second polypeptides of the multimeric polypeptide.
Claim 91 of 17/959,065 is drawn to a method of producing the multimeric polypeptide.
Claim 92 of 17/959,065 is drawn to a method of selectively modulating the activity of epitope-specific T cell.
The claims of 17/959,065 do not recite wherein the peptide epitope is a pathogen-associated epitope.
Botten et al teach identification of protective Lassa Virus (LASV) epitopes restricted by the MHC class I molecule HLA-A2. Botten et al teach including any of these epitopes in vaccine constructs (see entire reference, especially abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used a LASV pathogen-associated epitope taught by Botten et al as the epitope in the multimeric polypeptide recited in the claims of 17/959,065.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to assess the relative efficacy of each epitope, as the claims of 17/959,065 recite a peptide epitope in their construct along with an MHC molecule (b2m and MHC class I heavy chain) but are silent as to the identity of the peptide epitope, and the art reference Botten et al teach that these epitopes are protective in Lassa infection.
In addition, the instant claims that recite a linker that comprises glycine and serine are also included in this rejection because interposing glycine and serine comprising flexible peptide linkers between MHC class I components were well known in the art as is evidenced for example by Greten et al (J. Immunol. Meth. 2002, 271: 125-135, of record) who teach a glycine and serine comprising linker sequence between the peptide epitope and the amino terminal end of b2m, so it would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used a glycine and serine comprising linker in the construct used in the method recited in the claims of ‘518. The instant claims that recite more than one 4-1BBL polypeptide and in tandem arrangement, the instant claims are included in this rejection since the constructs recited in the claims of ‘518 may have more than one 4-1BBL MOD, and it would have been prima facie obvious to have arranged them in tandem.
Applicant’s arguments (of record in the amendment and response field 8/4/25 on pages 11-12) have been fully considered but are not persuasive.
However, the instant rejection ins not the only rejection remaining in the application.
12. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 18/656,531 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 100, 102-104 and 107-110 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-41 of 18/656,531.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 20-32 of 18/656,531 are drawn to a T cell modulatory multimeric polypeptide (T cell MMP) epitope conjugate/composition thereof comprising a T cell MMP and an epitope that may be a cancer, viral (i.e., a pathogen-associated) or self antigen-associated epitope conjugated thereto, wherein the T cell MMP comprising a first polypeptide comprising a b2m polypeptide having a chemical conjugation site, including a cysteine therein, and a second polypeptide comprising a MOD that is 4-1BBL, a MHC class I heavy chain polypeptide, and optional peptide linker and an optional Ig Fc polypeptide.
Claims 33-37 of 18/656,531 are drawn to a method of treatment comprising administering the T cell MMP epitope conjugate.
Claims 38 and 39 of 18/656,531 are drawn to one or more nucleic acids encoding a T cell MMP epitope conjugate and method of preparing it using the said one or more nucleic acids.
Claims 40 and 41 of 18/656,531 are drawn to a method comprising contacting the unconjugated T cell MMP with a peptide epitope presenting molecule.
The instant claims that recite a linker that comprises glycine and serine are also included in this rejection because interposing glycine and serine comprising flexible peptide linkers between MHC class I components were well known in the art as is evidenced for example by Greten et al (J. Immunol. Meth. 2002, 271: 125-135, of record) who teach a glycine and serine comprising linker sequence between the peptide epitope and the amino terminal end of b2m, so it would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used a glycine and serine comprising linker in the construct used in the construct recited in the claims of ‘531. The instant claims that recite more than one 4-1BBL polypeptide and in tandem arrangement are included in this rejection since the constructs recited in the claims of ‘531 may have more than one 4-1BBL MOD, and it would have been prima facie obvious to have arranged them in tandem. The instant claims that recite a dimer are included in this rejection because it would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have made a dimer in order to increase valency for an increase in avidity for the MHC/peptide portion to bind to a T cell, as was well known in the art before the filing date of the claimed invention, as is evidenced for instance by Greten et al who teach MHC-Ig Fc (dimeric) while the constructs recited in the claims of ‘531 also have Ig Fc portions thereof.
13. The prior rejection of record of claims 100 and 102-112 as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 82-101 of 17/958,904 in view of Chen et al (PNAS, 1991, 88: 110-114) and Yao et al (Vaccine, 2013, 31: 2289-2294) is hereby withdrawn, as ‘904 is presently abandoned.
14. Claims 100 and 102-112 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No.12,006,348 (of record) in view of Botten et al (J. Virol. 2006, 80(17): 8351-8361, of record).
The claims of US 12,006,348 are drawn to a T cell modulatory multimeric polypeptide (T cell MMP) comprising a first polypeptide comprising a b2m polypeptide, and a second polypeptide having in order at least one immunomodulatory polypeptides that is 4-1BBL, a class I MHC heavy chain, optional peptide linker, optional Ig Fc polypeptide, wherein the first and second polypeptides comprise chemical conjugations sites that are part of a linked attached thereto or within said polypeptides, and wherein the said conjugation sites are sites at which a molecule comprising an epitope peptide may be covalently bound, either directly or indirectly through a linker and positioned in the binding pocked of the T cell MMP for presentation to a cell bearing a TCR specific for the said epitope. The chemical conjugation sites may comprise and engineered cysteine, including present in the b2m polypeptide sequence.
The claims of US 12,006,348 do not recite that the epitope is attached to the T cell MMP, nor that the epitope is a pathogen-associated epitope.
Botten et al teach identification of protective Lassa Virus (LASV) epitopes restricted by the MHC class I molecule HLA-A2. Botten et al teach including any of these epitopes in vaccine constructs (see entire reference, especially abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used an epitope taught by Botten et al as the epitope and to have attached it to the multimeric polypeptide recited in the claims of US 12,006,348.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to assess the relative efficacy of each epitope, as the claims of US 12,006,348 recite a peptide epitope may be disposed in the peptide binding site of their construct via the conjugation sites formed by the MHC molecule (b2m and MHC class I heavy chain) but are silent as to the identity of the peptide epitope, while the art reference Botten et al teach that these epitopes are protective in Lassa infection.
The instant claims that recite a linker that comprises glycine and serine are also included in this rejection because interposing glycine and serine comprising flexible peptide linkers between MHC class I components were well known in the art as is evidenced for example by Greten et al (J. Immunol. Meth. 2002, 271: 125-135) who teach a glycine and serine comprising linker sequence between the peptide epitope and the amino terminal end of b2m, so it would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used a glycine and serine comprising linker in the construct used in the construct recited in the claims of ‘531. The instant claims that recite more than one 4-1BBL polypeptide and in tandem arrangement, the instant claims are included in this rejection since the constructs recited in the claims of US 12,006,348 may have more than one 4-1BBL MOD, and it would have been prima facie obvious to have arranged them in tandem. The instant claims that recite a dimer are included in this rejection because it would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have made a dimer in order to increase valency for an increase in avidity for the MHC/peptide portion to bind to a T cell, as was well known in the art before the filing date of the claimed invention, as is evidenced for instance by Greten et al who teach MHC-Ig Fc (dimeric) while the constructs recited in the claims of ‘531 also have Ig Fc portions thereof.
Applicant’s arguments (of record in the amendment and response filed 8/4/25 on pages 11-13) are not persuasive. Applicant’s arguments pertaining to provisional non-statutory double patenting are not applicable to an issued patent.
15. Claims 100 and 102-112 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 14 and 15-18 of U.S. Patent No. 11,702,461 (of record).
The claims of U.S. Patent No. 11,702,461 are drawn to a T cell modulatory multimeric polypeptide (TMMP)/pharmaceutical composition thereof/homodimer thereof comprising at least one heterodimer comprising a first polypeptide comprising an HBV (hepatitis B virus) peptide epitope (that is a pathogen-associated epitope), an optional linker, and b2m, and a second polypeptide comprising a 4-1BBL immunomodulatory polypeptide, a MHC class I heavy chain polypeptide, an optional linker, an Ig Fc polypeptide, an optional linker. A disulfide bond may be present between the first and second polypeptide, wherein the disulfide bond joins a cysteine residue in the b2m and a cysteine residue in the MHC heavy chain polypeptide. The TMMP may comprise more than one immunomodulatory polypeptides in tandem.
The instant claims that recite a linker that comprises glycine and serine are also included in this rejection because interposing glycine and serine comprising flexible peptide linkers between MHC class I components were well known in the art as is evidenced for example by Greten et al (J. Immunol. Meth. 2002, 271: 125-135) who teach a glycine and serine comprising linker sequence between the peptide epitope and the amino terminal end of b2m, so it would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used a glycine and serine comprising linker in the construct used in the construct recited in the claims of ‘461.
Applicant’s arguments (of record in the amendment and response filed 8/4/25 on pages 11-13) are not persuasive. Applicant’s arguments pertaining to provisional non-statutory double patenting are not applicable to an issued patent.
16. No claim is allowed.
17. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
18. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641