DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/21/2025 has been entered.
Disposition of Claims
Claims 1-2, 4, 7, 9, 14-15, 17-18, 20-21, 23, 28, 33, 38, 43, 47, 93-95, and 99 were pending. Claims 3-6, 8, 10-13, 16, 19, 22, 24-27, 29-32, 34-37, 39-42, 44-46, 48-92, and 96-98 are cancelled. Amendments to claims 1, 2, and 15 are acknowledged and entered. Claims 1-2, 7, 9, 14-15, 17-18, 20-21, 23, 28, 33, 38, 43, 47, 93-95, and 99 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20210393684A1, Published 12/23/2021. Amendments to the specification presented on 06/13/2024 are acknowledged and entered.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Response to Arguments
Applicant's arguments filed 10/21/2025 regarding the previous Office action dated 04/21/2025 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Claim Rejections - 35 USC § 101
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 1-2, 4, and 20 under 35 U.S.C. 101 is withdrawn in light of the amendments to the claims.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a pool of immunogenic peptides comprising HLA class I and class II- restricted Cytomegalovirus (CMV) peptide epitopes, wherein the peptide pool comprises each of the epitope amino acid sequences set forth in SEQ ID NOs. 25 to 29 and an adjuvant.
Claim 2 is drawn to a pool of immunogenic peptides comprising HLA class I and class II- restricted CMV peptide epitopes, and wherein the peptide pool comprises at least one peptide epitope derived from each of the CMV antigens pp50, pp65, IE-1, gB and gH and an adjuvant.
Claim 7 is drawn to a method of producing a preparation of polyfunctional cytotoxic T cells (CTLs), comprising: a) isolating a sample comprising CTLs; b) exposing said sample to the pool of immunogenic peptides of claim 1; and c) harvesting the CTLs.
Further limitations on the method of claim 7 are wherein the sample comprising CTLs comprises peripheral blood mononuclear cells (PBMCs) from a healthy donor or an immunocompromised donor (claim 9), wherein the immunocompromised donor is undergoing immunosuppressive therapy, a solid organ transplant recipient, or receiving anti-viral therapy (claim 99); wherein at step b), the sample comprising CTLs is incubated with the pool of immunogenic peptides for at least 14 days (claim 14), further comprising incubating the exposed sample of step b) with IL-21 on day 0 and/or IL-2 on day 2 (claim 15), further comprising adding IL-2 during step b) every three days (claim 17); further comprising administering the CTLs harvested from step c) to a subject suffering from a CMV infection (claim 18); and isolated CTLs prepared by the method of claim 7, wherein said isolated CTLs are those which are harvested in step c) of the method (claim 20).
Claim 21 is drawn to a method of treating CMV infection in a subject, comprising administering to the subject the CTLs of claim 20.
Further limitations on the method of claim 21 are wherein the CTLs administered to the subject are autologous (claim 23); wherein at least 5%, at least 10%, at least 20%, at least 60%, or at least 90% of the CTLs express CD107a (claim 28); wherein at least 5%, at least 10%, at least 20%, at least 60%, or at least 90%, of the CTLs express IFN-gamma (claim 33); wherein at least 5%, at least 10%, at least 20%, at least 60%, or at least 90% of the CTLs express TNF (claim 38); wherein at least 1%, at least 5%, at least 10%, or at least 20% of the CTLs express IL-2 (claim 43); and wherein at least 20%, at least 43%, at least 55%, or at least 90% of the CTLs express CD107a, IFN-gamma, and TNF (claim 47).
Claim 93 is drawn to a method of reducing CMV viral load in a subject that has received a solid organ transplant by administering to the subject the CTLs of claim 20.
Claim 94 is drawn to a method of treating or preventing CMV-associated end organ disease in a subject that has received a solid organ transplant by administering to the subject the CTLs of claim 20.
Claim 95 is drawn to a method of reducing or eliminating the need for anti-viral therapy in a subject that has received a solid organ transplant by administering to the subject the CTLs of claim 20.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claim 2 under 35 U.S.C. 102(a)(1) as being anticipated by Cobbold et. al. (US20140004081A1, Pub. 01/02/2014; CITED ART OF RECORD; hereafter “Cobbold”) is withdrawn in light of the amendments to the claims.
(New rejection – necessitated by amendment.) Claim 2 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Khanna-2005 et. al. (US20050019344A1; Pub. 04/28/2009; hereafter “Khanna-2005”.)
The Prior Art
Khanna-2005 teaches cytotoxic T cell (CTL) epitope peptides and polyepitope peptides from 14 distinct antigens of human cytomegalovirus (HCMV)(entire document; see abstract.) Said epitopes would preferentially have HLA class I (CTL/CD8+ T cell) epitopes, but may also have both CD4+ and CD8+ epitopes to have both CTL and helper T cell epitope stimulation ability (¶[0192]). Khanna-2005 teaches the peptides may be from known CMV antigens, such as pp50 (UL44)(¶[0143-0145]), pp65 (UL83)(¶[0146-0147]), glycoprotein B (gB or UL55)(¶[0152-0154]), glycoprotein H (gH or UL75)(¶[0155-0157]), and IE-1 (UL123)(¶[0158-0159]). Khanna-2005 teaches peptides from each of these antigens which align with 100% identity to instant peptide sequences (see table infra). Said peptides may comprise adjuvants (¶[0217][0261]). Therefore, Khanna-2005 teaches the limitations of instant claim 2.
Khanna-2005 teaches methods of producing CTLs through exposure of isolated peripheral blood mononuclear cells (PBMCs) isolated from healthy seropositive donors, followed by stimulating, expanding, and harvesting said CMV-specific CTLs (¶[0322-0326][0343]). Khanna-2005 teaches the T cells are cultured in the presence of a cytokine, such as IL-2 (¶[0088][0285]). The stimulated CTLs may be used to treat CMV infection in a subject (¶[0080]), such as a subject who has an HIV infection, is undergoing drug-induced immunosuppression (¶[0029]), or has undergone an organ transplant (¶[0030][0089][0332]), and may be autologous (¶[0105]) or allogenic (¶[0124]). The stimulated CTLs can have their activity measured through the expression of such markers as IFN-gamma (¶[0068]) or IL-2 (¶[0285]).
For at least these reasons, Khanna-2005 teaches the limitations of instant claim 2 and anticipates the invention encompassed by said claim.
(New rejection – necessitated by amendment.) Claim 2 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sampson et. al. (US20160213771A1; Pub. 07/28/2016; hereafter “Sampson”) as evidenced by Khanna-2005 et. al. (US20050019344A1; Pub. 04/28/2009; hereafter “Khanna-2005”.)
The Prior Art
Sampson teaches compositions, methods, and kits for eliciting an immune response to at least one CMV antigen expressed by a cancer cell, in particular for treating and preventing cancer (entire document; see abstract.) Sampson teaches the peptides would be 800 amino acids or fewer, and would range in size from 800 amino acids to 6 amino acids (¶[0120]). Sampson teaches the CMV peptide epitopes would comprise a mix of HLA class I and II peptides, as the immunologically active peptides would be useful to stimulate both CD8+ T cells and CD4+ T cells (¶[0094]). Sampson teaches the CMV epitopes would be derived from CMV proteins such as gB (UL55), IE1 (UL123), pp65 (UL83), and gH (UL75)(¶[0091-0093]), and would further include those antigens taught by Khanna-2005, which is incorporated by reference in its entirety (¶[0095]). Khanna-2005 teaches the peptide pools may comprise adjuvants (¶[0102]). As Khanna-2005 teaches that the CMV peptide pool may comprise adjuvants and peptides from gB, IE1, pp65, gH, and UL44 (pp50)(see detailed teachings supra of Khanna-2005), Sampson, as evidenced by the teachings of Khanna-2005, teaches the limitations of instant claim 2. As shown in the table below, Sampson or Khanna-2005 teach all except 7 of the epitopes of instant SEQ ID NOs: 1-31.
Instant
SEQ ID NO:
CMV Protein
Sequence
Sampson
SEQ ID NO:
Khanna-2005
SEQ ID NO:
1
pp50 (UL44)
VTEHDTLLY
140
165
2
pp65
YSEHPTFTSQY
N/A
70
3
pp65
NLVPMVATV
132
5
4
IE1
VLEETSVML
180
101
5
IE1
YILEETSVML
N/A
YILEETSVM (SEQ ID NO: 18)
6
IE1
AYAQKIFKIL
187
116
7
Pp65
QYDPVAALF
141
33
8
Pp65
TPRVTGGGAM
151
88
9
Pp65
RPHERNGFTVL
N/A
89
10
IE1
ELRRKMMYM
N/A
112
11
IE1
ELKRKMIYM
N/A
N/A
12
IE1
QIKVRVDMV
194
113
13
IE1
DELRRKMMY
N/A
N/A
14
Pp65
IPSINVHHY
158
67
15
Pp65
CPSQEPMSIYVY
N/A
66
16
Pp65
CEDVPSGKL
N/A
48
17
Pp65
HERNGFTVL
N/A
9
18
IE1
EEAIVAYTL
N/A
N/A
19
Pp65
QEFFWDANDIY
N/A
56
20
Pp65
TRATKMQVI
N/A
62
21
gB
YAYIYTTYL
N/A
189
22
Pp65
QAIRETVEL
145
80
23
IE1
CRVLCCYVL
190
N/A
24
gH
HELLVLVKKAQL
N/A
249
25
gB
DYSNTHSTRYV
N/A
191
26
Pp65
QEFFWDANDIYRIFA
N/A
107
27
gB
CMLTITTARSKYPYH
N/A
N/A
28
Pp65
PLKMLNIPSINVHHY
163
N/A
29
Pp65
EHPTFTSQYRIQGKL
N/A
70
30
Pp65
AGILARNLVPMVATV
135
N/A
31
IE1
KARAKKDELR
N/A
N/A
Sampson teaches wherein samples from a patient comprising CTLs are isolated, exposed to the peptide pools, resulting stimulated CTLs are harvested and then re-infused back into the same or different subject (¶[0102]). Sampson teaches the dosage will depend on the health of the subject (¶[0153-0154]), and PBMCs can be harvested and stimulated from healthy patients, immunosuppressed patients undergoing transplants, and those with cancer (¶[0041][0045][0308][0321][0357]). Sampson teaches the CTLs can be expanded within 14 days (¶[0308]) and that said cells could be incubated with IL-2 on day 3 for 48 hours (¶[0044][0302]). The CTLs can be given to a patient with an active or latent CMV infection (¶[0101][0352]) and can be an autologous lymphocyte transfer (ALT) (¶[0359][0362]) or an allogenic transfer (¶[0102]). The cells after ex vivo stimulation would be analyzed for IFN-gamma production, TNF-alpha production, IL-2 production, and polyfunctionality through analysis of granzyme activation marker CD107a (¶[0041]; Fig. 7). The CTLs can also be used in transplant recipients to reduce their susceptibility to CMV infection (¶[0096][0230][0346-0350]; Table 2).
For at least these reasons, Sampson, as evidenced by Khanna-2005, teaches the limitations of instant claim 2 and anticipates the invention encompassed by said claim.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 1, 4, 7, 9, 14-15, 17-18, 20-21, 23, 33 under 35 U.S.C. 103 as being unpatentable Cobbold as applied to claim 2 above, and further in view of Sylwester et. al. (Sylwester AW, et. al. J Exp Med. 2005 Sep 5;202(5):673-85.; hereafter “Sylwester”), Dander et. al. (Dander E, et. al. Exp Hematol. 2008 Apr;36(4):473-85. Epub 2008 Feb 8.; CITED ART OF RECORD; hereafter “Dander”), Sijmons et. al. (Sijmons S, et. al. PLoS One. 2014 Apr 22;9(4):e95501. and associated deposit Sijmons S, et. al. Regulatory protein IE1 [Human betaherpesvirus 5]. GenBank: AHB19584.1. Dep. 29 Apr 2014.; hereafter “Sijmons”); and Hall et. al. (Hall CE, et. al. PLoS One. 2017 Aug 11;12(8):e0178763.; hereafter “Hall”) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 21, 23, 28, 33, 38, 43, 47, 93-95, and 99 under 35 U.S.C. 103 as being unpatentable over Sylwester, Cobbold, Dander, Sijmons, and Hall as applied to claims 1-2, 4, 7, 9, 14-15, 17-18, 20-21, 23, 33 above, and further in view of Khanna et. al. (US20150273051A1, Pub. 10/01/2015; hereafter “Khanna”) is withdrawn in light of the amendments to the claims.
(New rejection – necessitated by amendment.) Claims 1, 7, 9, 14-15, 17-18, 20-21, 23, 33 are rejected under 35 U.S.C. 103 as being unpatentable over Sampson and Khanna-2005 as applied to claim 2 above, and further in view of Sylwester et. al. (Sylwester AW, et. al. J Exp Med. 2005 Sep 5;202(5):673-85.; CITED ART OF RECORD; hereafter “Sylwester”), Sijmons et. al. (Sijmons S, et. al. PLoS One. 2014 Apr 22;9(4):e95501. and associated deposit Sijmons S, et. al. Regulatory protein IE1 [Human betaherpesvirus 5]. GenBank: AHB19584.1. Dep. 29 Apr 2014.; CITED ART OF RECORD; hereafter “Sijmons”); Cobbold et. al. (US20140004081A1, Pub. 01/02/2014; CITED ART OF RECORD; hereafter “Cobbold”); Dander et. al. (Dander E, et. al. Exp Hematol. 2008 Apr;36(4):473-85. Epub 2008 Feb 8.; CITED ART OF RECORD; hereafter “Dander”); and Hall et. al. (Hall CE, et. al. PLoS One. 2017 Aug 11;12(8):e0178763.; CITED ART OF RECORD; hereafter “Hall”.)
The Prior Art
The teachings of Khanna-2005 and Sampson have been set forth supra. While Khanna-2005 and Sampson teach the generation of CMV peptide pools which comprise peptides from the CMV proteins UL44, pp65, gB, gH, and IE-1, as well as said peptide pools further comprising adjuvants, and while Khanna-2005 and Sampson teach many of the same peptides of the instant claims, neither Khanna-2005 nor Sampson teach every peptide as comprised within instant SEQ ID NOs: 1-31. However, important epitopes from CMV were known and described in the art, as evidenced by the further teachings of Sijmons, Cobbold, Sylwester, Dander, and Hall.
Cobbold teaches T cell antigens, especially T cell antigens from cytomegalovirus (entire document; see esp. reference claims 1, 10-12; ¶[0040][0069-0070]). Cobbold teaches the antigens from CMV (aka HHV5) can be from IE-1, UL55 (gB), UL83 (pp65), pp50, and UL75 (gH), and that short peptides from said antigens may be used (¶[0070-0073]). Cobbold teaches HLA Class II-restricted CMV epitope sequences that are 100% identical to instant SEQ ID NOs: 24, 25, 27 and 30, and peptides identical to instant SEQ ID NOs: 1-4, 8-15, 18, and 23 as HLA class I-restricted CMV epitopes (¶[0072-0075]). Cobbold teaches compositions which comprise one or more of these peptides, and that the compositions may be pharmaceutical compositions comprising pharmaceutically acceptable carriers, diluents, or excipients, such as sterile or pyrogen free water or saline (¶[0070][0153-0156][0160-0175]). Cobbold teaches peptide pools of CMV antigens, which are 15-mers from such CMV proteins as gB, IE1, and pp65, and teaches the predominant CD4+ and CD8+ T cell responses for each CMV ORF (¶[0070]). Cobbold teaches these peptides may be used in methods of adoptive or re-directed immunotherapy (entire document; see ¶[0002][0006-0008][0076-0078]).
Instant
SEQ ID NO:
Cobbold
SEQ ID NO:
Peptide
CMV
Protein
1
44
VTEHDTLLY
pp50
2
20
YSEHPTFTSQY
pp65
3
21
NLVPMVATV
pp65
4
4
VLEETSVML
IE-1
8
31
TPRVTGGGAM
pp65
9
32
RPHERNGFTVL
pp65
10
9
ELRRKMMYM
IE-1
11
10
ELKRKMIYM
IE-1
12
11
QIKVRVDMV
IE-1
13
16
DELRRKMMY
IE-1
14
33
IPSINVHHY
pp65
15
35
CPSQEPMSIYVY
pp65
18
18
EEAIVAYTL
IE-1
23
8
CRVLCCYVL
pp65
24
60
HELLVLVKKAQL
gH
25
55
DYSNTHSTRYV
gB
27
56
CMLTITTARSKYPYH
gH
30
53
AGILARNLVPMVATV
pp65
Sylwester teaches that they generated a CMV peptide pool for every CMV ORF (entire document; see abstract.) Sylwester teaches that they generated a CMV peptide pool to determine an overall response to CMV infection, and included overlapping 15-mer peptides from open reading frames (ORFs) UL55 (gB), UL83 (pp65), UL86, UL99, UL153, and UL32 (p. 682, left col., ¶2). Sylwester teaches the sequences for UL55 and UL83 used in their studies (Supp. Table 1; see below); a search of said sequences notes that SEQ ID NOs: 25-29 were all present at 100% identity. Consecutive 15mer peptides, overlapping by 10 amino acids, were designed for each ORF (p. 683, left col., ¶3). Therefore, Sylwester teaches the peptide pools may comprise peptides from an individual ORF, such as gB or pp65, or a peptide pool comprised of peptides from multiple CMV ORFs.
pp65 (UL83): (underlined in order SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 26)
MESRGRRCPEMISVLGPISGHVLKAVFSRGDTPVLPHETRLLQTGIHVRVSQPSLILVSQYTPDSTPCHRGDNQLQVQHTYFTGSEVENVSVNVHNPTGRSICPSQEPMSIYVYALPLKMLNIPSINVHHYPSAAERKHRHLPVADAVIHASGKQMWQARLTVSGLAWTRQQNQWKEPDVYYTSAFVFPTKDVALRHVVCAHELVCSMENTRATKMQVIGDQYVKVYLESFCEDVPSGKLFMHVTLGSDVEEDLTMTRNPQPFMRPHERNGFTVLCPKNMIIKPGKISHIMLDVAFTSHEHFGLLCPKSIPGLSISGNLLMNGQQIFLEVQAIRETVELRQYDPVAALFFFDIDLLLQRGPQYSEHPTFTSQYRIQGKLEYRHTWDRHDEGAAQGDDDVWTSGSDSDEELVTTERKTPRVTGGGAMAGASTSAGRKRKSASSATACTSGVMTRGRLKAESTVAPEEDTDEDSDNEIHNPAVFTWPPWQAGILARNLVPMVATVQGQNLKYQEFFWDANDIYRIFAELEGVWQPAAQPKRRRHRQDALPGPCIASTPKKHRG
gB (UL55): (underlined in order SEQ ID NO: 25, SEQ ID NO: 27)
MESRIWCLVVCVNLCIVCLGAAVSSSSTSHATSSTHNGSHTSRTTSAQTRSVYSQHVTSSEAVSHRANETIYNTTLKYGDVVGVNTTKYPYRVCSMAQGTDLIRFERNIICTSMKPINEDLDEGIMVVYKRNIVAHTFKVRVYQKVLTFRRSYAYIYTTYLLGSNTEYVAPPMWEIHHINKFAQCYSSYSRVIGGTVFVAYHRDSYENKTMQLIPDDYSNTHSTRYVTVKDQWHSRGSTWLYRETCNLNCMLTITTARSKYPYHFFATSTGDVVYISPFYNGTNRNASYFGENADKFFIFPNYTIVSDFGRPNAAPETHRLVAFLERADSVISWDIQDEKNVTCQLTFWEASERTIRSEAEDSYHFSSAKMTATFLSKKQEVNMSDSALDCVRDEAINKLQQIFNTSYNQTYEKYGNVSVFETSGGLVVFWQGIKQKSLVELERLANRSSLNITHRTRRSTSDNNTTHLSSMESVHNLVYAQLQFTYDTLRGYINRALAQIAEAWCVDQRRTLEVFKELSKINPSAILSAIYNKPIAARFMGDVLGLASCVTINQTSVKVLRDMNVKESPGRCYSRPVVIFNFANSSYVQYGQLGEDNEILLGNHRTEECQLPSLKIFIAGNSAYEYVDYLFKRMIDLSSISTVDSMIALDIDPLENTDFRVLELYSQKELRSSNVFDLEEIMREFNSYKQRVKYVEDKVVDPLPPYLKGLDDLMSGLGAAGKAVGVAIGAVGGAVASVVEGVATFLKNPFGAFTIILVAIA VVIITYLIYTRQRRLCTQPLQNLFPYLVSADGTTVTSGSTKDTSLQAPPSYEESVYNSGRKGPGPPSSDASTAAPPYTNEQAYQMLLALARLDAEQRAQQNGTDSLDGQTGTQDKGQKPNLLDRLRHRKNGYRHLKDSDEEENV
Both Cobbold and Sylwester teach CMV compositions comprising 15mer peptides, and teach that said peptides may be from any CMV ORF, including gB, pp65, IE1, gH (UL75), and pp50. Cobbold teaches peptides which are 100% identical to instant SEQ ID NOs: 24, 25, 27 and 30, and peptides identical to instant SEQ ID NOs: 1-4, 8-15, 18, and 23 as HLA class I-restricted CMV epitopes. Sylwester teach ORFs which comprise SEQ ID NOs: 25-29 at 100% identity, however, said 15mers of Sylwester do not all appear to comprise the claimed sequences in full (e.g. overlapping 15mers of the pp65 sequence would mean SEQ ID NO: 28 would be truncated at the C-terminus by 1 aa).
Dander teaches T cell epitopes from CMV proteins that align with 100% identity to those of the instant invention, and at least one that is 100% identical save for a 2aa deletion (SEQ ID NOs: 26, 28-29, See Table 1, See table below). Dander teaches peptides from CMV proteins, such as pp65, pp50, and IE1 (Table 1). Dander teaches collection of leukocytapheresis products from 13 CMV-seropositive donors, wherein said products are separated into monocytes or lymphocytes, and then CMV-specific T-cell lines were generated (p. 476, left col., “Generation of CMV-specific T-cell lines”), wherein said CMV-specific T-cell lines were incubated with a pooled peptide library identified as immunogenic for CD4 and CD8 responses with HLA class I and II antigens from CMV proteins pp65, pp50, pp150, and IE1 for 24 days, and CD8+ stimulated T cells were isolated and analyzed for their bioactivity (pp. 474-6, “Materials and Methods”, See esp. “Peptide library”, “Preparation of CMV-specific T-cell lines”, “Flow cytometric analysis”, and “Staining with MHC-peptide multimers”; instant claims 7, 9, 14, 20). Said T-cells were incubated with IL-2 starting at day +7 and was added at 50 U/mL until the end of the culture (instant claims 15 and 17.) Dander teaches their experiments allow for the use of said expanded T cells in vivo as they were expanded under GMP conditions and did not use virus-infected or CMV lysate pulsed antigen presenting cells (p. 474, left col., ¶3) and that adoptive transfer of CMV-specific T cells can be used upon isolation of those T cells which express the correct pattern of adhesion molecules which allow them to migrate to the infected cell sites (p. 474, left col., ¶2; instant claim 18, 21). Dander teaches the T cells administered were autologous (p. 477, left col., ¶2; instant claim 23). Dander teaches analysis of IFN-gamma production, wherein anywhere from 36-66% of the CD8+ T cells produced IFN-gamma (Fig. 4B; instant claim 33).
Instant
SEQ ID NO:
Dander
CMV Protein
Sequence
25
N/A
gB
DYSNTHSTRYV
26
KYqeffwdandiyri
pp65
qeffwdandiyrifa
27
N/A
gH
CMLTITTARSKYPYH
28
100%
pp65
PLKMLNIPSINVHHY
29
100%
gH
EHPTFTSQYRIQGKL
Sylwester at Supplemental Table 1 teaches full-length sequences for IE1, pp50 (UL44), gB, gH, and pp65 which comprise SEQ ID NOs: 1-4, 6-10, and 12-31 at 100% identity (see table below) and comprise SEQ ID NOs: 5 and 11 with 1 aa change (YVLEETSVML) and 2 aa change (ELRRKMMYM), respectively (see table below; See attached appendix for full length sequences of IE1, pp50, gB, gH, and pp65). Sylwester only utilized sequences from laboratory strains of CMV known at the time of publication, and highlighted the importance of looking at different ORFs and strain-specific sequences (p. 680, ¶ bridging cols.) Sylwester also notes the broad T cell response to CMV infection is beyond the previously noted pp65 and IE-1 antigens, and directly teaches that a variety of CMV antigens stimulate a variety of T cell responses (p. 681, rt. Col.)
Sijmons teaches that further clinical and laboratory isolates have been sequenced, and teaches further techniques for high-throughput sequencing of CMV clinical isolates (entire document; see abstract.) Sijmons teaches AHB19584.1, which is an IE1 sequence that comprises mutations compared to Sylwester’s AD169 sequence, and teaches a sequence that comprises SEQ ID NO:5 at 100%.
Instant
SEQ ID NO:
CMV Protein
Sequence
Taught with 100%
Identity by:
1
pp50
VTEHDTLLY
Sylwester
2
pp65
YSEHPTFTSQY
Sylwester
3
pp65
NLVPMVATV
Sylwester
4
IE1
VLEETSVML
Sylwester
5
IE1
YILEETSVML
Sijmons
6
IE1
AYAQKIFKIL
Sylwester
7
Pp65
QYDPVAALF
Sylwester
8
Pp65
TPRVTGGGAM
Sylwester
9
Pp65
RPHERNGFTVL
Sylwester
10
IE1
ELRRKMMYM
Sylwester
11
IE1
ELKRKMIYM
Cobbold
12
IE1
QIKVRVDMV
Sylwester
13
IE1
DELRRKMMY
Sylwester
14
Pp65
IPSINVHHY
Sylwester
15
Pp65
CPSQEPMSIYVY
Sylwester
16
Pp65
CEDVPSGKL
Sylwester
17
Pp65
HERNGFTVL
Sylwester
18
IE1
EEAIVAYTL
Sylwester
19
Pp65
QEFFWDANDIY
Sylwester
20
Pp65
TRATKMQVI
Sylwester
21
gB
YAYIYTTYL
Sylwester
22
Pp65
QAIRETVEL
Sylwester
23
IE1
CRVLCCYVL
Sylwester
24
gH
HELLVLVKKAQL
Sylwester
25
gB
DYSNTHSTRYV
Sylwester
26
Pp65
QEFFWDANDIYRIFA
Sylwester
27
gB
CMLTITTARSKYPYH
Sylwester
28
Pp65
PLKMLNIPSINVHHY
Sylwester
29
Pp65
EHPTFTSQYRIQGKL
Sylwester
30
Pp65
AGILARNLVPMVATV
Sylwester
31
IE1
KARAKKDELR
Sylwester
Hall teaches analysis of CMV peptides that also have human peptide matches (entire document; see abstract), and teaches that the entire set of known CMV sequences and ORFs was input into a database to cross match relevant HLA class I bound CMV peptides and determine which peptides had a corresponding peptide in the human genome (p. 4, ¶3). Hall therefore teaches that there were bioinformatics tools and programs available to determine peptide antigens from all known CMV sequences.
Given that generation of CMV peptide pools to stimulate CD4 and CD8 T cells were known in the art at the time of filing, as evidenced by Khanna-2005 and Sampson and further evidenced by Sylwester and Cobbold, and given that Khanna-2005 and Sampson teach generation of CMV peptide pools comprising the known important CMV antigens pp65, UL44, gH, IE-1, and gB, given that bioinformatics to identify important CMV antigens were known in the art, as evidenced by Hall, and given that CMV sequences and antigens were known in the art, as evidenced by Khanna-2005, Sampson, Sylwester, Sijmons, Cobbold, Dander, and Hall, one of skill in the art would have found it obvious to arrive at the combination of peptides of instant claim 1, namely peptide pools that included the sequences of SEQ ID NOs: 1-31. Further, as both Sampson and Khanna-2005 teach generation of peptide pools comprising HLA class I and II epitopes from UL44, gB, gH, IE-1, and pp65, and teach methods of expanding CTLs from CMV seropositive individuals, and given that protocols for this CTL stimulation were known in the art, as evidenced by the teachings of Sampson, Khanna-2005, and Dander, one of skill would find it obvious to arrive at the methods and products of instant claims 7, 9, 14-15, 17-18, 20-21, 23, 28, 33, 38, 43, 47, 93-95, and 99.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Khanna-2005 or Sampson in order to add specific CMV peptide antigens to their CMV antigen pools, thereby providing a pool of peptides that would theoretically target a larger swath of antigens important within different HLA populations, especially given that bioinformatics tools to prevent alloreactivity were known in the art, as taught by Hall. One would have been motivated to do so, given the suggestion by Dander, Cobbold, Khanna-2005, Sampson, Sylwester, and Sijmons as to the antigens to use from the specific CMV proteins. There would have been a reasonable expectation of success, given the knowledge that there were known sequence variants for CMV proteins, as taught by Sylwester and Sijmons, and also given the knowledge that these sequences could be easily determined and analyzed, as taught by Sijmons and Hall. There would have been further reasonable expectation of success in arriving at the claimed methods and CTL populations, as protocols for CTL stimulation and expansion were known in the art, as evidenced by the teachings of Khanna-2005, Sampson, and Dander. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant's arguments filed 10/21/2025 have been fully considered but they are not entirely persuasive. It should be noted that while the anticipation rejection regarding Cobbold was withdrawn, the teachings of Cobbold were still relevant to the obviousness rejections, and were therefore utilized in the new obviousness rejection herein. Likewise, the original obviousness rejection was withdrawn, but the same art references utilized in the prior obviousness rejection were utilized in the new obviousness rejection. In the interest of compact prosecution, the arguments regarding the teachings of Cobbold, Khanna-2005, Sampson, Sylwester, Sijmons, Dander, and Hall will be addressed as applicable to the new rejection herein.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
With respect to the anticipation teachings over Cobbold, as Cobbold fails to teach the inclusion of an adjuvant in the peptide pool, the anticipation rejection was withdrawn. Applicant argues that Cobbold fails to teach the presence of both HLA class I and class II epitopes in the same peptide pool. Cobbold nowhere specifically excludes the presence of one class when another is present, and at ¶[0060] notes that when they refer to “T cell”, they are including all types of T cells, including CD4+ and CD8+. At ¶[0061-0064], the language continues to include eliciting a response from both T cell types, and notes at ¶[0064] the antigen may bind to both class I and class II. While Cobbold is no longer the primary reference, and Khanna-2005 and Sampson clearly teach peptide pools which comprise mixtures of MHC class I and II antigens, it is not entirely convincing that Cobbold fails to teach peptide compositions with only one class of antigen. Applicant also argues that while Cobbold teaches antigens from CMV, Cobbold fails to teach each within the same composition. Again, as Cobbold is no longer the primary reference, and Khanna-2005 and Sampson clearly cure this deficiency, Cobbold is not relied upon for this teaching, but for the rationale above, and that Cobbold teaches compositions which “comprise” the noted antigens, it is unconvincing that Cobbold teaches away from or fails to teach compositions which could comprise multiple antigens.
Applicant then argues that the remaining references fail to cure the deficiencies of Cobbold. As Cobbold is no longer the primary reference, this general argument is moot.
Applicant argues that while Sylwester teaches generation of overlapping CMV peptides to determine the immune response to each known CMV ORF, that Sylwester fails to provide motivation to generate the peptide pool of claim 1 or 2, and fails to teach all of SEQ ID NOs: 1-31. With respect to the new obviousness rejection, it should be noted that the obvious nature of claim 1 is not solely in view of Sylwester, Dander, Sijmons, or Hall and Khanna-2005 and Sampson, but the combination of all references - Khanna-2005, Sampson, Sylwester, Cobbold, Sijmons, Dander, and Hall.
Applicant additionally argues surprising and unexpected results. Applicant points to the data in Fig. 1A-E and Table 3, in that CMV-specific T cells were successfully expanded from 20 out of the 21 patient blood samples, and the T cells were predominantly CD3+CD8+ with a median specificity of 51.2%. Applicant argues enhanced functionality with in vitro expansion, with clinical responses showing improved responsiveness to antiviral therapy and reduction or resolution of active CMV infection. However, such an argument is not commensurate in scope with the breadth of the claimed invention. The peptide pool was that which only consisted of those CMV peptides which consisted of SEQ ID NOs: 1-31, with at least one patient receiving a supplement of the IE-1 epitope HLA-B*31:01 KARAKKDELR (KAR) (Table 1, ¶[0033-0034]). The stimulation was done in the presence of IL-21, using a specific stimulation method that comprised further IL-2 supplementation (¶[0121]). The specific CMV peptide pools were exposed to patients who had undergone solid organ transplantation (SOT) and were CMV seropositive, with active or persistent CMV disease or replication (¶[0113]). It is not clear if healthy CMV seropositive patients were tested for their ability to stimulate CD4+ and/or CD8+ T cells in the presence of the peptide pools. It is not clear if the stimulated peptides were tested in allogenic T cell therapy for their usefulness. It is not clear if other adjuvants would have the same effect on the T cell stimulation as IL-21. It is not clear if the peptides could include additional amino acids beyond those used in Table 1 (e.g. if said peptides could be a part of a longer, multi-epitope polypeptide or comprised within longer native peptide sequences) or if the compositions could include/comprise peptides beyond SEQ ID NOs: 1-31. There is nothing surprising or unexpected about the pools of peptides claimed in instant claims 1 or 2, and the methods are not surprising in light of the prior art and the breadth of the instant claims. Khanna-2005 and Sampson teach the majority of the peptides comprised in the peptide pool of instant claims 1 and 2, and the art either taught those which were not present or provided motivation, teachings, and skills as to how to generate CMV peptide pools of HLA class I and II antigens with immunogenic importance. One suggestion to overcome the obvious nature is to claim compositions which consist of peptide sequences and adjuvants which provided the surprising/unexpected results, wherein said peptides consist of the sequences of SEQ ID NOs: 1-31. As the criticality of parameters to arrive at the unexpected or surprising results is not identified, specifically with regards to the claimed methods, and there is no functional language in the product claims that would aid in an argument of surprising or unexpected results, such an argument is unpersuasive in light of the prior art.
For at least these reasons, Applicants arguments are not persuasive, and the claims remain rejected as being anticipated or obvious for the reasons outlined above.
Double Patenting
The text regarding nonstatutory double patenting was presented in a previous Office action.
(Rejection maintained in part – necessitated by amendment.) Claims 1-2, 7, 9, 14-15, 17-18, 20-21, 23, 28, 33, 38, 43, 47, 93-95, and 99 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-51 and 56-57 of copending Application No. 18/798,113 (reference application) in view of Sylwester and Khanna (supra). The rejection of instant claim 4 is withdrawn in light of the cancellation of said claim. The rationale behind this rejection was set forth in a previous Office action and will not be repeated herein.
Response to Arguments
Applicant has requested that the non-statutory obviousness-type double patenting rejection be held in abeyance until allowable subject matter is indicated in the present application. However, said rejection must be maintained as a matter of record until the appropriate terminal disclaimers have been filed, or until the claims have been amended in such a way as to not claim patently identical subject matter.
Conclusion
No claims are allowed.
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/RACHEL B GILL/Primary Examiner, Art Unit 1671