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 OFFICE ACTION
This Office Action is in response to the papers filed on 04 August 2025.
CLAIMS UNDER EXAMINATION
Claims 1, 4-7, 9-10, 14-18 20 and 21 are pending and have been examined on their merits.
PRIORITY
Foreign Priority document EP17195324.3 filed on 06 October 2017 is acknowledged.
WITHDRAWN REJECTIONS
The previous rejections have been withdrawn due to claim amendment and cancellation.
REJECTIONS
The rejections have been modified to address new claim 21 and amended claim 20.
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.
Claims 1, 4-7, 9-10, 16-18 and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Willerslev-Olsen et al. (Bacterial Toxins Fuel Disease Progression in Cutaneous T-Cell Lymphoma. Toxins (Basel). 2013 Aug; 5(8): 1402–1421) in view of Loessner et al. (Polypeptide mixes with antibacterial activity. US20150118189A1) as evidenced by (Rahman et al. Endolysin, a Promising Solution against Antimicrobial Resistance. Antibiotics 2021, 10, 1277 pages 123).
Willerslev-Olsen teaches that in patients with cutaneous T-cell lymphoma (CTCL), bacterial infections constitute a major clinical problem caused by compromised skin barrier and a progressive immunodeficiency. Indeed, the majority of patients with advanced disease die from infections with bacteria, e.g., Staphylococcus aureus. Bacterial toxins such as staphylococcal enterotoxins (SE) have long been suspected to be involved in the pathogenesis in CTCL (Abstract).
Staphylococcus aureus is a major source of morbidity in CTCL causing chronic or recurrent skin infections and life-threatening systemic infections such as sepsis, pneumonia and intra-abdominal infections. S. aureus is renowned for its ability to produce staphylococcal enterotoxins (SE) (also known as superantigens). Superantigens are characterized by their ability to activate large fractions of T lymphocytes by crosslinking MHC class 2 molecules and T-cell receptors (independently of antigen specificity of the TCR and the antigen-peptide-binding groove in the MHC) thereby circumventing normal antigen processing and presentation (page 1408, last paragraph).
In several small series and case studies, elimination of S. aureus infection with antibiotics was associated with a rapid clinical improvement: in some patients treatment resulted in complete clinical response with no residual skin involvement by CTCL.
While the art teaches administration of antibiotics able to treat S. aureus infection in patients with CTCL, the art does not teach administration of an endolysin specific for S. aureus.
Loessner teaches a composition used as an antimicrobial agent (Abstract). Loessner et al. teach a composition comprising a combination of enzymatic domains ([0004]). The invention relates to a pharmaceutical or medical composition for the treatment of a condition related to Staphylococcus ([0136]). Preferably, the invention relates to a pharmaceutical or medical composition for the treatment of an infectious disease caused by a bacterium, preferably a bacterium of the genus Staphylococcus, more preferably a bacterium of the species S. aureus. Preferably, said infectious disease is a skin infection ([0136]). Loessner teaches the invention relates to a first, second, third and/or further polypeptide which exhibits a lytic activity of at least 30, 40, 50, 60, 70, 80,90, 100, 150 or 200% or more of a lytic activity of S. aureus bacteriophage d2638a endolysin (Ply2638 endolysin identified by SEQID NO: 2) encoded by SEQID NO: 1. As evidenced by Rahman et al., endolysins are a class of antibiotics (see page 2, second paragraph, lines 4-5).
It would have been obvious to try treating CTCL by administering an endolysin specific for Staphylococcus aureus. One would have been motivated to do so since Willerslev-Olsen teaches CTCL can be improved by treating Staphylococcus aureus with antibiotic and Loessner teaches an endolysin (an antibiotic) can be used to treat the same bacteria. One would have had a reasonable expectation of success since Loessner teaches the compositions can be used to treat skin infections by S. aureus. One would have expected similar results since both references teach treating skin infections caused by Staphylococcus aureus using antibiotics. Because administration of endolysin is rendered obvious, it would be expected to treat cancer as claimed.
Claim 1 has been amended to recite the proliferative effect of S. aureus alpha-toxin on malignant and non-malignant T cells. As evidenced by the instant specification, alpha toxin is a protein inherent to S. aureus (supra). Because Willerslev-Olsen is directed to patients with S. aureus, administration of the endolysin would inherently have the effect recited in claim 1. Therefore claim 1 is rendered obvious.
Loessner teaches the following ([0086]):
Also preferred is a combination according to the present invention, wherein a first polypeptide according to the present invention has at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identity with SEQ ID NO: 60, a second polypeptide according to the present invention as at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identity with SEQ ID NO: 72 and a third polypeptide according to the present invention has at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identity with SEQ ID NO: 54.
Therefor the art teaches a composition comprising SEQ ID NO: 72.
SEQ ID 72 cited in Table 2 for artificial construct HXaM23-LST_M23-LST_CWT-NM3 reads on the endolysin SEQ ID 72 of the instant invention (see Table 1).
Therefore claims 4-5 are included in this rejection.
Willerslev-Olsen is directed to humans and Loessner teaches administration to humans ([0140]). Therefore claim 6 is included in this rejection.
As evidenced by the instant specification, CTCL is a mucosa associated cancer ([0018]). Therefore claim 7 is included in this rejection.
Loessner teaches pharmaceutical acceptable carrier ([0130]). Said carrier is broadly interpreted to be an excipient. Therefore claim 9 is included in this rejection.
Loessner teaches a mixture of endolysins that treat S. aureus. The art teaches the following ([0086]):
Also preferred is a combination according to the present invention, wherein a first polypeptide according to the present invention has at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identity with SEQ ID NO: 60, a second polypeptide according to the present invention as at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identity with SEQ ID NO: 72 and a third polypeptide according to the present invention has at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identity with SEQ ID NO: 54.
The first polypeptide is broadly interpreted to read on a second anti-cancer medicament. Therefore claim 10 is included in this rejection.
As evidenced by the instant specification, CTCL is a mucosa associated cancer ([0018]). Therefore claims 16-18 are included in this rejection.
Regarding new claim 21: The teachings of the prior art are reiterated.
It would have been to treat a CTCL patient by administering an endolysin specific for S. aureus. Willerslev-Olsen teaches CTCL can be improved by treating S. aureus with an antibiotic and Loessner teaches an endolysin (an antibiotic) can be used to treat the same bacteria. The skilled artisan would administer an endolysin with lytic activity against S. aureus to treat a condition caused by S. aureus. One would have had a reasonable expectation of success since Loessner teaches the compositions can be used to treat skin infections by S. aureus. One would have expected similar results since both references treat skin infections caused by S. aureus using antibiotics. Because the active method step is rendered obvious, it would be expected to take away the selective advantage of malignant T cells to proliferate as recited in preamble of the claim. Therefore claim 21 is rendered obvious. Because the claimed method is rendered obvious, it would result in the mechanism of killing S. aureus cells recited in claim 20.
Therefore Applicant’s Invention is rendered obvious as claimed.
APPLICANT’S ARGUMENTS
The arguments made in the response filed on 04 August 2025 are acknowledged. The Applicant maintains the arguments previously set forth. The arguments state the inventors have demonstrated two surprising effects not taught in the prior art:
(1) Staphylococcus aureus alpha-toxin does not inhibit proliferation of malignant T-cells in CTCL, while Staphylococcus aureus alpha-toxin does inhibit proliferation of non-malignant T-cells. Presence of Staphylococcus aureus alpha-toxin thus provides an advantage for malignant T-cells to proliferate. Killing Staphylococcus aureus by an endolysin will treat CTCL by taking away the alpha-toxin and hence the selective advantage of malignant T-cells to proliferate; and
(2) Staphylococcus aureus alpha-toxin inhibits CD8" effector cells mediated killing of CTCL cells (modeled by MART-1 peptide pulsed Mac1 target cells). Killing Staphylococcus aureus by an endolysin will treat CTCL by taking away the alpha-toxin that inhibits CD8" effector cells.
The Applicant argues that because these two effects were not taught by the prior art, the claimed method would not have been obvious.
EXAMINER’S RESPONSE
The arguments are not persuasive. While the claim recites how the endolysin functions in vitro (inhibiting T-cell proliferation), the only active method step is administration of an endolysin specific for S. aureus to a patient with cancer.
Willerslev-Olsen teaches staphylococcal toxins are involved in the pathogenesis of cutaneous T-cell lymphoma (CTCL; cancer). The majority of patients with advanced disease die from skin infections with bacteria, including Staphylococcus aureus. Willerslev-Olsen teaches administration of antibiotics able to treat S. aureus infection in patients with CTCL.
Loessner teaches a pharmaceutical composition for the treatment of a skin infection caused by Staphylococcus aureus. The composition comprises an endolysin specific for S. aureus. As evidenced by Rahman et al., endolysins are a class of antibiotics (see page 2, second paragraph, lines 4-5).
It would have been obvious to treat CTCL by administering an endolysin specific for Staphylococcus aureus. One would have been motivated to do so since Willerslev-Olsen teaches CTCL can be improved by treating Staphylococcus aureus with antibiotic and Loessner teaches an endolysin (an antibiotic) can be used to treat the same bacteria. One would have had a reasonable expectation of success since Loessner teaches the compositions can be used to treat skin infections by S. aureus. One would have expected similar results since both references teach treating skin infections caused by Staphylococcus aureus using antibiotics. Because the active method step is rendered obvious, endolysin treatment would be expected to take away the ability of malignant T-cells to proliferate as claimed.
Claims 1, 4-7, 9-10, 14-18 and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Nguyen et al. (Cutaneous T -cell lymphoma and Staphylococcus aureus colonization. 2008 American Academy of Dermatology 949-952) in view of Loessner et al.
Nguyen teaches Cutaneous T-cell lymphoma (CTCL) is the most common lymphoma of the skin. Infection is a common complication of this disease and is the leading cause of death. The most common pathogen of cutaneous infections and bacteremias in CTCL patients is Staphylococcus aureus (SA). Infection may be in part due to an impaired skin barrier as well as a decrease in the repertoire of normal circulating T cells and immunosuppression. See Background section. Nguyen teaches treating SA colonization and cutaneous infections may help reduce the severity of CTCL (see page 952, left column, first paragraph). It is noted Nguyen teaches MRSA can be found in CTCL patients (Table II).
While the art teaches treating S. aureus infection may help reduce the severity of CTCL, the art does not teach administration of an endolysin specific for S. aureus.
The teachings of Loessner are reiterated.
It would have been obvious to try treating CTCL with an endolysin specific for Staphylococcus aureus. One would have been motivated to do so since Nguyen teaches CTCL can be improved by treating Staphylococcus aureus and Loessner teaches an endolysin can be used to treat the same bacteria. One would have had a reasonable expectation of success since Loessner teaches the compositions can be used to treat skin infections by S. aureus. One would have expected similar results since both references teach treating skin infections caused by Staphylococcus aureus.
Claim 1 recites properties of S. aureus alpha-toxin. As evidenced by the instant specification, alpha-toxin is a protein inherently found in S. aureus (supra). Because Nguyen is directed to patients with S. aureus, it would be expected to have the effect recited in claim 1. Because administration of endolysin is rendered obvious, it would be expected to treat cancer as claimed. Therefore claim 1 is rendered obvious.
Loessner teaches the following ([0086]):
Also preferred is a combination according to the present invention, wherein a first polypeptide according to the present invention has at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identity with SEQ ID NO: 60, a second polypeptide according to the present invention as at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identity with SEQ ID NO: 72 and a third polypeptide according to the present invention has at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identity with SEQ ID NO: 54.
Therefor the art teaches a composition comprising SEQ ID NO: 72.
SEQ ID 72 cited in Table 2 for artificial construct HXaM23-LST_M23-LST_CWT-NM3 reads on SEQ ID 72 of the instant invention (see Table 1).
Therefore claims 4-5 are included in this rejection.
Loessner teaches the endolysin can be administered to humans ([0140]). Therefore claim 6 is included in this rejection.
As evidenced by the instant specification, CTCL is a mucosa associated cancer ([0018]). Therefore claim 7 is included in this rejection.
Loessner teaches pharmaceutical acceptable carrier ([0130]). Said carrier is broadly interpreted to be an excipient. Therefore claim 9 is included in this rejection.
Loessner teaches a mixture of endolysins that treat S. aureus. The art teaches the following ([0086]):
Also preferred is a combination according to the present invention, wherein a first polypeptide according to the present invention has at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identity with SEQ ID NO: 60, a second polypeptide according to the present invention as at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identity with SEQ ID NO: 72 and a third polypeptide according to the present invention has at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identity with SEQ ID NO: 54.
The first polypeptide is broadly interpreted to read on a second anti-cancer medicament. Therefore claim 10 is included in this rejection.
It would have been obvious to try treating an antibiotic resistant S. aureus since Nguyen teaches MRSA (hence, a methicillin resistant S. aureus) can be found in CTCL patients. Therefore claim 14 is included in this rejection. MRSA reads on claim 15.
As evidenced by the instant specification, CTCL is a mucosa associated cancer ([0018]). Therefore claims 16-18 are included in this rejection.
It would have been obvious to treat a CTCL patient by administering an endolysin specific for S. aureus. Nguyen teaches CTCL can be improved by treating S. aureus and Loessner teaches an endolysin can be used to treat the same bacteria. The skilled artisan would administer an endolysin with lytic activity against S. aureus to treat a condition caused by S. aureus. One would have had a reasonable expectation of success since Loessner teaches the compositions can be used to treat skin infections by S. aureus. One would have expected similar results since both references teach treating skin infections caused by Staphylococcus aureus using antibiotics. Because the active method step is rendered obvious, it would be expected to take away the selective advantage of malignant T cells to proliferate as recited in preamble of the claim. Therefore claim 21 is rendered obvious. Because the claimed method is rendered obvious, it would result in the mechanism of killing S. aureus cells recited in claim 20.
Therefore Applicant’s Invention is rendered obvious as claimed.
APPLICANT’S ARGUMENTS
The arguments made in the response filed on 04 August 2025 are acknowledged. The Applicant applies the arguments directed to Willerslev-Olsen to the rejection citing Nguyen.
EXAMINER’S RESPONSE
The arguments are not persuasive. Nguyen teaches infection is a common complication Cutaneous T-cell lymphoma (a skin cancer) and is the leading cause of death. The most common pathogen of cutaneous infections and bacteremias in CTCL patients is Staphylococcus aureus (SA). Nguyen teaches treating SA colonization and cutaneous infections may help reduce the severity of CTCL.
Loessner teaches a pharmaceutical composition for the treatment of a skin infection caused by Staphylococcus aureus. The composition comprises an endolysin specific for S. aureus.
It would have been obvious to try treating CTCL with an endolysin specific for Staphylococcus aureus. One would have been motivated to do so since Nguyen teaches CTCL can be improved by treating Staphylococcus aureus and Loessner teaches an endolysin can be used to treat the same bacteria. One would have had a reasonable expectation of success since Loessner teaches the compositions can be used to treat skin infections by S. aureus. One would have expected similar results since both references teach treating skin infections caused by Staphylococcus aureus.
Claim 1 recites properties of S. aureus alpha-toxin. As evidenced by the instant specification, alpha-toxin is a protein inherently found in S. aureus (supra). Because Nguyen is directed to patients with S. aureus, it would be expected to have the effect recited in claim 1. Because administration of endolysin is rendered obvious, it would be expected to treat cancer as claimed.
CONCLUSION
No Claims Are Allowed
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the APIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653