DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/18/2025 has been entered.
Priority
This application is a U.S. National Stage (371) application of PCT/US19/36073 filed on 06/07/2019 which claims priority to U.S. Provisional Application No. 62/681,929 filed on 06/07/2018.
Claim Status
Claims 1, 4, 7, 13-15, 19, 23, 25, 31 and 71 were previously presented. Claims 2-3, 6, 8, 10-12, 16 and 26 are original. Claims 5, 9, 17-18, 20-22, 27-30 and 32-70 are cancelled at the Applicant’s request. Claim 24 is withdrawn as being directed to a nonelected invention as acknowledged by the Applicant in the reply filed on 03/19/2024.
Thus, claims 1-4, 6-8, 10-16, 19, 23, 25-26, 31 and 71 are under examination.
New Rejections
Claim Rejections - 35 USC § 112
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.
Claims 1-4, 6-8, 10-16, 19, 23, 25-26, 31 and 71 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for lung cancer, does not reasonably provide enablement for all types of cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case where there is a relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. In the instant case, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. Specifically, the method for treating any cancer with an effective amount of any inhibitor of an immune checkpoint protein is overly broad and is not well supported by the specification.
The current disclosure does not satisfy the enablement requirement for treating a patient with different types of cancer and whether any necessary experimentation is "undue as discussed In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Regarding claim 1, the claim recites a method for treating cancer in a subject comprising administering an effective amount of an inhibitor of an immune checkpoint protein to said subject. The specification does not provide enough support for an artisan to perform the assay without undue additional experimentation as described in in re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1998) as appropriate. See also MPEP § 2164.01(a) and § 2164.04.
The breadth of the claims:
Claim 1 is drawn to treating any type of cancer by administering any inhibitor of any immune checkpoint protein in subjects where the subject has been determined to have increased level of immune checkpoint protein as compared to control by using a deglycosylating enzyme. Specifically, the subject has been determined to have an increased level of said immune checkpoint protein as compared to a control sample by a method comprising: (a) enzymatically deglycosylating proteins in a fixed sample obtained from said subject; (b) contacting said sample with an anti-immune checkpoint protein antibody; and (c) measuring the binding of the antibody to said immune checkpoint protein, thereby detecting the level of said immune checkpoint protein.
The nature of the invention:
The invention is about a method for treating cancer in a subject comprising administering an effective amount of an inhibitor of an immune checkpoint protein to said subject, wherein the subject has been determined to have an increased level of said immune checkpoint protein as compared to a control sample by a method comprising: (a) enzymatically deglycosylating proteins in a fixed sample obtained from said subject; (b) contacting said sample with an anti-immune checkpoint protein antibody; and (c) measuring the binding of the antibody to said immune checkpoint protein, thereby detecting the level of said immune checkpoint protein.
The state of the prior art:
Although there has been reports about treating one type of cancer as noted by Kazaz et al. for non-small lung cancer (Turk Thorac J 2017; 18: 101-7, Abstract), Morales-Betanzos et al. for human melanoma (MCP, Volume 16, Issue 10, October 2017, Pages 1705-1717, Abstract), and Li et al. for breast cancer (Cancer Cell 33, 187–201, February 12, 2018, Abstract), there is no prior art that describes the universal treatment of all types of cancer because of the complexity of cancer as a disease as noted by Gentles et al. (Cancer Res; 71(18) September 15, 2011, Page 5964, right column, second paragraph). Cancer is a variable disease and its clinical manifestation and treatment differs even from one patient to another based on multiple factors and that makes treatment response vary greatly as noted by Yang et al. (Clinical pharmacology & Therapeutics, Volume 88, Number 1, July 2010). It is understood from the prior art that while there have been dramatic improvements in the treatment of patients with cancer, it remains a challenge for clinicians on how to tackle each type of cancer and how to offer the best treatment in each case. Last, there are still challenges in targeting immune checkpoint proteins with inhibitors because there is a lack of information on the binding affinities to antigens on human immune cells and cancer cells as noted by Khan et al. (Journal of Oncology, Volume 2015, Article ID 847383, 15 pages, Epub 2015 Apr 28, page 11, left column, first paragraph). Khan noted that this information is needed to control the unforeseen variation in protein function from individual to individual (Page 11, left column, first paragraph).
Furthermore, in re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case here where there is a relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims of the instant application.
The level of one of ordinary skill:
Based on the complexity and unpredictability of cancer treatment as noted above by Gentles, Yang and Khan, the level of a person having ordinary skill in the art is not high enough to treat all types of cancer. Gentles noted that cancer has been successfully eradicated in a Petri dish but these results rarely translate to in vivo (Page 5963, left column, fifth paragraph). Gentles noted that tumor microenvironment play a role in deciding the behavior of cancer cells but is poorly understood (Page 5963, left column, fifth paragraph). Yang noted that there are fundamental challenges to cancer therapy because the consequences of target inhibition for protein networks in tumor and normal cells are unknown and considerable patient-to-patient variation is observed (Page 37, right column, first paragraph). And as noted above by Khan, there are unforeseen variations in protein function from individual to individual because of the lack of information on the binding affinities to antigens on human immune cells and cancer cells (Page 11, left column, first paragraph).
Thus, a person having ordinary skill in the art would not have been able to treat every type of cancer by administering any inhibitor of any immune checkpoint protein in human subjects.
The level of predictability in the art:
There is a high level of unpredictability in the response of patients to cancer treatment as noted above by Yang. Yang noted that there are fundamental challenges to cancer therapy because responses to specific therapies are less dramatic and specific in patients than had been hoped, often because the consequences of target inhibition for protein networks in tumor
and normal cells are unknown and considerable patient-to-patient variation is observed (Page 37, right column, first paragraph). Furthermore, Khan noted that there are unforeseen variations in protein function from individual to individual because of the lack of information on the binding affinities to antigens on human immune cells and cancer cells (Page 11, left column, first paragraph).
The amount of direction provided by the inventor:
As discussed above, the art acknowledges the complexity of cancer and thus the inventor needs to show how the method of the instant application will enable a skilled artisan to treat any type of cancer with any immune checkpoint inhibitor in a human subject.
The specification only gives two examples on how to detect PD-L1 in lung cancer and how deglycosylation enhances the detection of PD-L1 immune checkpoint protein (Page 36, Example 1). Example 1 teaches detecting PD-L1 after the removal of N-linked glycosylation (Pages 36-37). Example 2 teaches the type of cells and human tissues used to assess the detection of PD-L1 after deglycosylation (Page 43).
Examples 1 and 2 do not provide a plan or a method for how to treat every type of cancer and only shows detection of PD-L1 after deglycosylation in lung cancer cell lines and tissue blocks. Thus, the specification of the instant application fails to address a method for treating any type of cancer in a subject.
The existence of working examples:
There is a limited number of examples in the specification as noted above (Page 36, Example 1; page 43, Example 2). Example 1 of the specification is about the enhanced detection of PD-L1 after the removal of N-linked glycosylation from cancer cell lines, human tissue blocks, and human tissue microarray (Pages 36-37). Example 1 mainly shows the benefits of detecting PD-L1 after deglycosylation in Lung cancer (Pages 38-39)
Example 2 is about the type of cells used and human tissues used to assess the detection of PD-L1 after deglycosylation (Page 43).
The examples are directed to treating lung cancer from the cell lines and tissue studies. The examples do not teach treating all types of cancer.
Furthermore, there is no indication from the examples of the specification of the instant application that the broadly claimed method would work in any type of cancer with any inhibitor of any immune checkpoint protein because the examples are only teaching detecting PD-L1 after deglycosylation. Thus, the specification does not provide guidance with respect to treating any type of cancer with any immune checkpoint inhibitor and it cannot be assumed that the claimed method would work with any type of cancer and any immune checkpoint inhibitor.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
With the lack of teaching in prior art in regards to treating any cancer type, the PHOSITA is expected to face an unreasonable amount of experimentation. Furthermore, the complexity of cancer and the possible occurrence in different parts of the human body add another challenge to a PHOSITA or to a clinician.
Thus, the specification of the instant application does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with the claims of the instant application. Consequently, claims 1-4, 6-8, 10-16, 19, 23, 25-26, 31 and 71 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for lung cancer, does not reasonably provide enablement for all types of cancer.
Maintained Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art (PHOSITA) to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 6-8, 10-12, 16, 19, 23, 25-26, 31 and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Smithy et al. ("Predicting Response To Anti-Pd-1 Immunotherapy In Metastatic Melanoma" (2017), Yale Medicine Thesis, Digital Library, 2172, July 6, 2017) in view of Tom-Moy et al. (The FASEB Journal, Abstract, 01 April 2014) and Pardoll et al. (Nat Rev Cancer, 2012 Mar 22;12(4):252-264).
Regarding claim 1, Smithy teaches how a human subject with cancer such as diffuse large B cell lymphoma or non-small cell lung cancer has been determined to have an increased level of an immune checkpoint protein such as sPD-L1 as compared to a control sample (Page 16, third paragraph; page 17, first paragraph).
Smithy teaches how to enzymatically deglycosylate proteins with PNGase F in a cell line (Page 29, first paragraph).
Smithy teaches how to contact a sample with three commercially available antibodies to PD-L1 that are anti-immune checkpoint protein antibodies: E1L3N, E1J2J and SP142 to test their abilities to bind to PD-L1 based on its glycosylation status (Page 29, second paragraph; page 35, fourth paragraph).
Smithy teaches how to measure the binding of an antibody to an immune checkpoint protein such as PD-L1 and to detect the level of PD-L1 (Page 45, figure 12, detection of deglycosylated PD-L1 in five cell lines by Western blot with three anti-PD-L1 antibodies).
Regarding claims 7 and 8, Smithy teaches PD-L1 as the immune checkpoint protein (Page7, second paragraph; page 16, third paragraph; page 17, first paragraph).
Regarding claim 10, Smithy teaches how to contact a sample with a deglycosylation enzyme (Page 29, first paragraph).
Regarding claim 11, Smithy teaches that the deglycosylation enzyme removes N-linked glycosylation (Page 61, third paragraph).
Regarding claim 12, Smithy teaches that the deglycosylation enzyme is peptide-N-glycosidase (PNGase F) (Page 61, third paragraph).
Regarding claim 16, Smithy teaches how to perform Immunoblotting or Western Blotting (Figure 12, “detection of deglycosylated PD-L1 in five cell lines by Western blot with three anti-PD-L1 antibodies”).
Regarding claim 19, Smithy teaches how a cell line has been previously determined to have no or low expression of the immune checkpoint protein using a non-deglycosylated sample (Figure 12, “Detection of deglycosylated PD-L1 in five cell lines”).
Regarding claim 23, Smithy teaches the immune checkpoint as PD-L1 (Page7, second paragraph; page 16, third paragraph; page 17, first paragraph).
Regarding claim 25, Smithy teaches the immune checkpoint inhibitor as PD-1 inhibitor (Page 35, second paragraph).
Regarding claim 26, Smithy teaches Nivolumab as a PD-1 inhibitor (Abstract; Page 35, second paragraph).
Regarding claim 31, Smithy teaches the cancer as melanoma or lung cancer (Page 6, first paragraph; page 33, first paragraph; page 56, first paragraph).
Regarding claim 1, Smithy does not teach treating cancer in a subject by administering an effective amount of an inhibitor of an immune checkpoint protein to a subject.
Smithy does not teach how to deglycosylate proteins in a fixed sample obtained from a subject.
Regarding claim 2, Smithy does not teach how to use a fixed sample with formalin or with paraformaldehyde.
Regarding claim 3, Smithy does not teach using a formalin-fixed paraffin-embedded (FFPE) sample. Regarding claim 4, Smithy does not teach how to use a fixed sample that is isolated from saliva, blood, urine, normal tissue or tumor tissue.
Regarding claim 6, Smithy does not teach a fixed sample that does not comprise live cells. Regarding claim 10, Smithy does not teach contacting a fixed sample.
Regarding claim 19, Smithy does not teach getting a sample from a subject.
Regarding claim 23 and 71, Smithy does not teach using an inhibitor to PD-L1.
Regarding claims 1-2, Tom-Moy teaches the ability to deglycosylate proteins from a fixed sample with formalin from a subject (Abstract).
Regarding claim 3, Tom-Moy teaches deglycosylating proteins from an FFPE sample (Abstract).
Regarding claim 4, Tom-Moy teaches using a fixed sample from a tissue (Abstract).
Regarding claim 6, Tom-Moy teach using a fixed sample that does not comprise live cells (Abstract).
Regarding claim 10, Tom-Moy teaches deglycosylating proteins using a fixed sample (Abstract).
Regarding claims 1, 23 and 71, Pardoll teaches to treat cancer in a subject by administering an effective amount of an inhibitor to PD-L1 such as MDX-1105 (Page 255, table 1, “PDL1”, “MDX-1105”, “Multiple mAbs”).
Regarding claim 19, Pardoll teaches how to have samples from a human subject (Page 258, first paragraph).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the deglycosylation method of Tom-Moy with the in situ deglycosylation method of Smithy to improve the method of treating a subject with lung cancer because Tom-Moy teaches an approach on how to deglycosylate proteins from a fixed sample such as one obtained from tumor surgeries (Abstract), and Smithy further noted that it would also be useful to perform in situ deglycosylation on tumor samples (Page 61, fourth paragraph). Smithy teaches that there is a need for further optimization of the deglycosylation protocol to determine if glycosylation has any effect over the performance of an immunohistochemistry assay which is used to stain fixed tumor samples (Page 62, first paragraph).
A skilled artisan would have been further motivated to combine the treatment method of Pardoll with the combined invention of Tom-Moy and Smithy to improve the method of treating a subject with lung cancer because Pardoll teaches using an inhibitor to an immune checkpoint protein to treat a subject with cancer (Page 260, second and third paragraph, “Although the clinical experience with PD1 antibodies is currently much less extensive than with CTLA4 antibodies, the initial results look extremely promising”) and noted that the response to such an inhibitor is extremely promising but does not seem to be consistent (Page 260, third paragraph, “In the first Phase I clinical trial with a fully human IgG4 PD1 antibody, there were some cases of tumour regression, including mixed responses, partial responses and a complete response”). Smithy attributed such variability of response to an inhibitor to an immune checkpoint protein due to the glycosylation status of immune checkpoint proteins (Page 10, second paragraph) and offered a method on how to deglycosylate a protein in a cell line before adding an antibody to an immune checkpoint protein (Page 29, first paragraph).
A PHOSITA would have had a reasonable expectation of success in combining the methods of Tom-Moy, Pardoll and Smithy based on the methods being in the field of cancer detection and response to treatment. It would have been obvious for a PHOSITA to use the inhibitor of Pardoll after assessing the glycosylation status of immune checkpoint proteins in a fixed sample as shown by Tom-Moy and Smithy because it offers the promise of an effective treatment to a lung cancer patient.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Smithy et al. ("Predicting Response to Anti-Pd-1 Immunotherapy in Metastatic Melanoma" (2017), Yale Medicine Thesis, Digital Library, 2172, July 6, 2017), Tom-Moy et al. (The FASEB Journal, Abstract, 01 April 2014) and Pardoll et al. (Nat Rev Cancer, 2012 Mar 22;12(4):252-264) as applied to claim 1 above, and further in view of Xiong et al. (Journal of Proteome Research 2003, 2, 618-625).
Regarding claim 13, Smithy does not teach incubating the sample with PNGase F for 12-16 hours.
However, regarding claim 13, Xiong teaches incubating the sample with PNGase F for 12 hours. (Page 620, fourth paragraph).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine deglycosylation method of Xiong with the combined method of Tom-Moy, Pardoll and Smithy to improve the method of treating a subject with lung cancer because Xiong teaches that incubating a sample with PNGase F for 12 hours leads to a complete and successful deglycosylation (Page 620, fourth paragraph) and uses his method to aid in disease detection in many types of glycopathology and cancer (Page 624, right column, third and fourth paragraphs). A PHOSITA would have had a reasonable expectation of success in combining the methods of Xiong, Tom-Moy, Pardoll and Smithy based on the methods being in the field of cancer detection and response to treatment. It would have been obvious for a PHOSITA to use the inhibitor of Pardoll after assessing the glycosylation status of immune checkpoint proteins in a fixed sample as shown by Xiong, Tom-Moy and Smithy because it offers the promise of an effective treatment to a lung cancer patient.
Claims 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Smithy et al. ("Predicting Response to Anti-Pd-1 Immunotherapy in Metastatic Melanoma" (2017), Yale Medicine Thesis, Digital Library, 2172, July 6, 2017), Tom-Moy et al. (The FASEB Journal, Abstract, 01 April 2014) and Pardoll et al. (Nat Rev Cancer, 2012 Mar 22;12(4):252-264) as applied to claim 1 above, and further in view of New England Biolabs (NEB) (New England Biolabs, Protocols, PNGase F Protocol, Jul 31, 2014).
Regarding claims 14-15, the teachings and suggestions of Smithy, Tom-Moy and Pardoll are discussed previously.
Moreover, regarding claims 14-15, Smithy teaches using deglycosylation reagents from New England Biolabs under denaturing conditions (Page 29, first paragraph).
Regarding claims 14-15, Smithy does not teach the concentration of PNGase F to be 5%.
Regarding claims 14-15, New England Biolabs teaches that the concentration of PNGase F is 5% when performing deglycosylation under denaturing conditions (1 µl of PNGase F to 20 µl of total reaction volume) (New England Biolab Protocol, denaturing reaction conditions, steps 4 and 5).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine deglycosylation protocol of New England Biolabs with the combined invention of Tom-Moy, Pardoll and Smithy to improve the method of treating a subject with lung cancer because New England Biolabs provide specific amounts of reagents to achieve optimal deglycosylation based on the type of the protein studied (Second paragraph, “Reactions may be …”), and provide typical reaction conditions to make optimization easier to perform (Second paragraph, “Typical reaction conditions …”). A PHOSITA would have had a reasonable expectation of success in combining the methods of New England Biolabs, Tom-Moy, Pardoll and Smithy based on the methods being in the field of studying protein glycosylation as it relates to cancer treatment. It would have been obvious for a PHOSITA to use the inhibitor of Pardoll after assessing the glycosylation status of immune checkpoint proteins in a fixed sample as shown by New England Biolabs, Tom-Moy and Smithy because it offers the promise of an effective treatment to a lung cancer patient.
Response to Arguments
Regarding the rejection of claims under 35 U.S.C. 103, regarding obviousness, the Applicant argued against such a rejection. Applicant's arguments filed on 12/18/2025 have been fully considered but they are not persuasive for the following reasons:
First, the Applicant alleged that Pardoll does not teach or suggest any methods by which to select which patients other than to identify that biomarkers for guiding the choice of immune checkpoint inhibitor for a particular tumor will be a challenge. The Applicant further questioned the guidance that is provided by Pardoll to select an immune checkpoint inhibitor.
This argument is not persuasive because Pardoll acknowledged the presence of inconsistency of response to an immune checkpoint inhibitor and is not obliged to provide guidance on how to overcome such inconsistency of response. While Pardoll teaches using an inhibitor of an immune checkpoint protein to treat a subject with cancer (Page 260, second and third paragraph), Pardoll further notes that the response to such an inhibitor does not seem to be consistent (Page 260, third paragraph).
Second, the Applicant alleged that Smithy performed deglycosylation assays on protein lysates, not tissue samples, and found that all three antibodies detect both glycosylated and deglycosylated PD-L1 by Western blot assay.
However, Smithy clearly suggested repeating the protocol on tissue samples and with different antibodies as noted above (Page 61, last paragraph; page 62, first paragraph).
Third, the Applicant alleged that although Smithy proposed that repeating the experiment by immunohistochemistry (IHC) assay would be informative, as the conditions for antigen binding are quite different on Western blot compared to formalin fixed paraffin embedded (FFPE) tissue, he did not obtain reproducible results to draw any conclusions because due to the lack of a good protocol.
However, Smithy attributed the lack of reproducible results to the use of specific antibodies and not to the method itself. Smithy further suggested using different antibodies as noted above (Page 61, last paragraph).
Fourth, The Applicant alleged that Smithy is merely contemplating that different methods could be assessed does not suggest to a person skilled in the art that altering the glycosylation state of an immune checkpoint protein in clinical samples would serve to increase the predictive power of immune checkpoint protein detection for selecting patients for treatment with immune checkpoint inhibitors. The Applicant alleged that indeed, as the methods used by Smithy did not work, it appears to in fact to teach away from any further optimization of the protocol.
This argument is not persuasive because Smithy provided a possible explanation for the results of their experiments and attributed it to antibodies and suggested further optimization of the protocol with a different set of antibodies from the FDA-approved IHC assays for PD-L1. Smithy further mentioned that as all three antibodies tested bound both glycosylated and deglycosylated forms, it is unlikely their respective epitopes are affected by glycosylation, and hence the suggestion of using a different set of antibodies.
Fifth, The Applicant alleged that while Smithy does state that “further optimization of this protocol would help to determine whether glycosylation status has an effect on the performance of a given IHC assay”, a skilled artisan would not have been able to predict that removal of PD-L1 N-linked glycosylation by enzymatic digestion of tissue samples would increase homogeneity of target proteins and quantitatively facilitate antibody-based detection of a more precise estimation of PD-L1 levels to prevent false-negative readouts in clinical settings.
This argument is not persuasive because PD-L1 is known in prior art to be heavily N-linked glycosylated as noted by Morales-Betanzos (MCP, Volume 16, Issue 10, October 2017, Pages 1705-1717; Abstract, “most abundant glycan modification yielded a very low PD-L1 IHC estimate, thus suggesting that N-glycosylation may affect IHC measurement and PD-L1 function.”). A skilled artisan would have been motivated based on the recommendation of Smithy and findings of Pardoll to adapt the deglycosylation protocol of Tom-Moy using a different set of antibodies (i.e., FDA antibodies) to further look at the effects of deglycosylating PD-L1 on detecting a signal for PD-L1 in a tissue after administering an immune checkpoint protein (ICP) inhibitor. The success of Smithy experiments in this case is irrelevant because Smithy acknowledged the results and offered an explanation (Pages 61-62, “To further illustrate the clinical relevance of PD-L1 glycosylation …”) that resonates well with what Pardoll has found (Page 260, third paragraph). Specifically, Smithy suggested performing in situ deglycosylation of tumor samples and to compare the efficacy of several antibodies in this setting (Pages 61-62, “it would also be useful to perform in situ …”).
Sixth, The Applicant alleged that the present studies performed an optimized deglycosylation assay followed by IHC staining of PD-L1 on patient samples to demonstrate that deglycosylation of PD-L1 can serve as a biomarker to predict the efficacy of anti-PD-1. The Applicant alleged that these findings were surprising and unexpected in view of Smithy.
This argument is not persuasive because Smithy suggested optimizing the deglycosylation assay and IHC staining of PD-L1 on tumor samples (Pages 61-62, “it would also be useful to perform in situ …”). The results of the instant application are not unexpected in view of Smithy because Smithy clearly suggested performing such set of experiments to provide an explanation for poor response to ICP therapy.
Seventh, The Applicant alleged that a finding of obviousness requires that "the combination [yield] nothing more than predictable results to one of ordinary skill in the art ". MPEP 214 3IA (emphasis added); see also Croes, Inc. v. Int 'l Trade Comm 'n, 598 F.3d 1294, 1309 (Fed. Cir. 2010) ("Even if the [claims at issue] were a combination of known elements according to their established functions ... it yields more than predictable results [and therefore is] non-obvious.").
The argument is not persuasive because it is acknowledged by prior art of Morales-Betanzos that PD-L1 is heavily N-linked glycosylated (Abstract), and Tom-Moy teaches that deglycosylating a protein in tissues enhances the specific binding of antibodies to glycoproteins (Abstract). Thus, the results of the instant case are not unpredictable in view of the prior art.
Eighth, the Applicant alleged that Pardoll teaches the use of immune checkpoint inhibitors for cancer therapy but provides no teaching for the analysis of patient samples for the selection of patients that will respond to the immune checkpoint therapy. Thus, a person skilled in the art would not be motivated to combine Pardoll with Smithy.
This argument is not persuasive because the Applicant is advised to look at references in combination. The Applicant is reminded to look at the teachings of references in combination as it has been noted in the MPEP. Regarding the rejection of claims under 35 U.S.C. 103 and 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).
Ninth, Similarly, the Applicant alleged that Tom-Moy is cited as teaching deglycosylation of proteins in a fixed sample obtained from a subject. The Applicant alleged that Tom-Moy teaches CA19-9 and BG-8 as glycoprotein antigens and that glycans can be removed from FFPE tissue. The Applicant alleged that there is no teaching or suggestion for the deglycosylation of immune checkpoint proteins by the present methods to result in accurate prediction of clinical response to immune checkpoint inhibitor therapy.
This argument is not persuasive because as noted above, the Applicant is reminded to look at the teachings of references in combination as it has been noted in the MPEP.
Tenth, the Applicant alleged that based on the teachings of the cited prior art references, a skilled artisan would not have found it predictable that deglycosylation improves detection of immune checkpoint proteins, such as PD-L1, such that detection of an increased level of the deglycosylated immune checkpoint protein would identify a patient as eligible for cancer treatment with an immune checkpoint inhibitor.
This argument is not persuasive because of the previous discussions that clearly noted the need to understand the reason for getting inconsistent therapy response with inhibitors of immune checkpoint proteins (ICP) as noted by Smithy and Pardoll. Furthermore, in response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Smithy suggested performing in situ deglycosylation of tumor samples and to compare the efficacy of several antibodies in this setting (Pages 61-62, “it would also be useful to perform in situ …”), and Tom-Moy teaches that deglycosylating a protein in tissues enhances the specific binding of antibodies to glycoproteins (Abstract). Thus, the results of the instant case are not unpredictable in view of the prior art.
In conclusion, a skilled artisan would have been motivated to combine the above methods and to optimize the deglycosylation conditions of Smithy’s experiments in view of prior art to reach the invention of the instant application.
Consequently, the previous rejections of claims 1-4, 6-8, 10-16, 19, 23, 25-26, 31 and 71 under 35 U.S.C. 103, regarding obviousness, is maintained.
Conclusion
No claims are allowed.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678