DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Claims 1-19 are pending.
Claims 1-19 are examined on the merits.
Claim Objections
3. Claim 1, 6 and 11 are objected to because of the following informality: each independent claim should recite the full meaning of the acronym prior to the abbreviation. For instance, on line 5 of claim 1 it should be recited “…signal peptide peptidase-like 3 (SPPL3)…”.
Correction is required.
Claim Interpretation
4. The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
5. 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. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
6. This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are: “…anti-CD19 antibodies configured to recognize CD19 comprising the reference glycosylation state, see claim 19, lines 3 and 4 of the Claims submitted February 7, 2023, page 19. The specification on page 2, lines 12-15; page 3, last paragraph (para.) cites the same; as well as other citations of similar language on page 3, last sentence; page 10, last para.; page 11, first para. and lines 20-22; and page 12, lines 10-15. There is no clear definition or functional equivalents, thereof identified in the specification. The Specification is silent with respect to any structural elements and corresponding structure, but rather cites a compound or antibody to be implemented in the claimed invention absent of structure that performs the recognition.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 112
7. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
8. Claims 1-5, 12-14 and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
a. Claims 1, 2 and 12 recite the term, “substantially”. It is not clear how much in amount and/or level in the expression or activity of a biomarker is significant or important to impact critical decisions, i.e. resistance to immunotherapy and/or selecting treatment.
Likewise, the term, “similar” recited in claim 12, step a. is vague and indefinite. It is not clear how alike or correlative the CD19 glycosylation states between an individual’s malignant B cells and reference should or should not be to determine which CD19-targeted immunotherapy should be selected for treatment.
Accordingly, the metes and bounds cannot be determined.
b. Claim 19 recites “…anti-CD19 antibodies configured to recognize CD19 comprising the reference glycosylation state.”, see last two lines of the claim. It is not clear how these antibodies are arranged and/or their structure is designed in order to identify CD19 in a glycosylated state. The metes and bounds cannot be determined.
Claim Rejections - 35 USC § 101
9. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
10. The claimed invention is directed to non-statutory subject matter. The claim(s) (claims 1-5 and 11-19) does/do not fall within at least one of the four categories of patent eligible subject matter because they read on a judicial (i.e., a law of nature, a natural phenomenon, or an abstract) without significantly more.
The claimed invention (claims 1-5 and 11-19) is directed to a judicial exception and/or natural phenomenon without significantly more. The claim(s) recite(s) a method of detecting a biomarker(s) level in malignant B cells, the glycosylation state biomarker, CD19 and/or expression or activity of biomarker, SPPL3 and/or any combination thereof. The biomarker(s) is/are compared to a reference biomarker(s). A substantial difference between the biomarker(s) level and the reference biomarker(s) level is indicative of the B cell malignancy’s resistance to immunotherapy.
Furthermore, the claimed invention reads on selecting a B cell malignancy treatment comprising detecting a biomarker(s) level in malignant B cells, the glycosylation state biomarker, CD19 and/or expression or activity of biomarker, SPPL3 and/or any combination thereof. The biomarker(s) are compared to a reference biomarker(s). A comparison between the biomarker(s) level and the reference biomarker(s) level is indicative of the B cell malignancy treatment that should be selected.
Moreover, differences between the glycosylation state of CD19 (hyperglycosylated or hypoglycosylated) compared to reference glycosylation state in malignant B cells or SPPL3 expression/activity in malignant B cells substantially increased/decreased compared to reference expression/activity of SPPL3 in malignant B cells is indicative of the B cell malignancy is resistant to immunotherapy.
The judicial exception reads assaying a biomarker(s) level in an individual’s malignant B cells, comparing it to a reference biomarker level and based on differences between these levels is indicative of immunotherapy treatment resistance and selecting a B cell malignancy treatment. This judicial exception is not integrated into a practical application because gathering information and observing the difference in candidate cancer biomarker(s) level(s) between an individual’s biological sample and a reference level(s) required to use the correlation does not add a meaningful limitation to the method as they are insignificant extra-solution activity. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
The analysis as set forth in the 2019 Guidance is as follows:
Step 1: Yes, claims are drawn to a method which is one of the four statutory categories, a process.
Step 2A, prong 1: Yes, the claims recite/describe/set forth a judicial exception. The claims describe the relationship between the difference in an individual’s biomarker(s), CD19 and/or SPPL2 level(s) within malignant B cells and reference biomarker(s) level is indicative of resistance to immunotherapy, as well as the treatment to select. Furthermore, assayed differences in CD19 glycosylation states between an individual’s B cell malignancy and reference sample is indicative of the treatment to select.
Step 2A, prong 2: No, the judicial exception is not integrated into a practical application. The claims do not rely on or use the exception here. Once differences in expression and/or activity of biomarker(s) SLLP3 and states of CD19 glycosylation within the individual’s malignant B cells sample and a reference, there are no additional elements or combination of additional elements to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Determining and selecting are mental steps/ processes, thereby the claims encompass abstract ideas and involve performing mental steps.
Step 2B: There is no inventive concept present in the clams. The steps of analyzing the level of candidate cancer biomarker(s) in a biological sample and assessing a glycosylation pattern is established by well understood, routine conventional methods, and in addition they are pre-solution activity, i.e. data gathering necessary to perform the correlation. The following claims and steps inform one of ordinary skilled in the art, the comparison and the level of biomarker(s) identifies an individual as requiring treatment. The claims do not recite additional elements that amount to significantly more than the judicial exception. Accordingly, these claims are not be eligible under step 2A or step 2B.
Claims 1-5 and 11-19 are drawn to a non-statutory method having a "natural principle" as a limiting element or step without reciting additional elements/steps that integrate the natural principle into the claimed invention such that the natural principle is practically applied, and are sufficient to ensure that the claim amounts to significantly more than the natural principle itself. In the instant case, the "natural principle" is: detecting biomarkers, a glycosylation state of CD19, SPPL3 expression or activity in malignant B cells as compared to a reference biomarker level and difference in biomarker levels between the malignant B cells and the reference level is indicative of the B cell malignancy will be resistant to immunotherapy and what treatment to select.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because assaying candidate cancer biomarkers, as well as their expression and/or activity does not add significantly more and is not an inventive concept. Because methods for making such determinations were well known in the art, these steps simply tell researchers to engage in well-understood, routine, conventional activity previously engaged in by scientists in the field. Such activities are normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such law. The claims do not add significantly more to the natural phenomenon because the claims do not require a novel reagent, apparatus of incorporate a novel treatment based on the correlation.
A claim that focuses on use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, and added something significant to, the natural principle itself. See Mayo, 101 USPQ2d at 1966. Recited elements such as “detecting”, “comparing”, “determining” and “selecting” based on the natural principle impose no meaningful limit on the performance of the claimed invention. As set forth the claims do not impose meaningful limits on the performance of the claimed invention. Patents cannot be obtained on subject matter identified by the courts as being exempted from eligibility (i.e., laws of nature, natural phenomenon, and abstract ideas). Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the recited natural principle. The claims do not "practically apply" the natural principle; rather, the claims "simply inform" the natural principle to one performing routine active method steps and do not amount to significantly more than the natural principle itself. Thus, the technology used by the instant claims is well-known in the art and does not contribute significantly more to the judicial exception. See the 2019 Revised Patent Subject Matter Eligibility Guidance and Federal Register https://www.federalregister.gov/documents/2019/10/18/2019-22782/october-2019-patent-eligibility-guidance-update; and FDsys.gov.
Claim Rejections - 35 USC § 102
11. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
12. Claim(s) 6-10 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bondanza et al., WO 2020/020841 A1 (published 30 January 2020). Bondanza discloses treating B-cell malignancies comprising solid, haematopoietic or lymphoid tumors with one glycosylation inhibitor in combination with an immunotherapy, preferably a CAR-T cell therapy, see page 1, 1st paragraph (para.); page 3, lines 30 and 31; and page 7, lines 11-21. The CAR T targets CD19, see page 17, lines 23 and 24. With the administration of the disclosed treatment, T cell recognition of CD19 would improve, activation of CAR t cell effector function would increase and CD19-targeted CAR T anti-tumor cytotoxicity would be enhanced.
The B-cell malignancies include “…chronic lymphocytic leukemia (CLL), acute leukemias, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL),..B cell prolymphocytic leukemia,… Burkitt’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma,…[most] non-Hodgkin’s lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, or preleukemia,”, see page 6, lines 30 and 31; and page 7, lines 11-21.
C19-targeted CAR T therapies are able to treat patients with refractory B-cell malignancies, see page 1, lines 12-22. Moreover, Kymriah® (tisagenlecleucel) and Yescarta® (axicabtagene ciloleucel) are also disclosed, which are able to treat peaediatric and young adult relapse/refractory B-cell ALL and adult relapsed/refractory large B-cell lymphoma, respectively, see page 1, lines 20-22; and page 20, lines 11-16.
Claim Rejections - 35 USC § 103
13. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
14. Claim(s) 1-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Heard et al., (Blood 138 (Supplement 1): 1721-1723, 5 November 2021), and further in view of Bot et al., US 2021/0161959 A1 (effectively filed November 6, 2020) and Fischer et al., (J. Immunotherapy 40 (5): 187-195, June 2017). Heard teaches “[g]el-shift analysis demonstrating that loss of SPPL3 results in hyperglycosylation of CD19 while over-expression (SPPL3KO+) results in hypoglycosylation.”, see page 1722, Figure 1e.
“[Heard] confirmed decreased glycosylation of CD19 (Figure 1e), and found that this resulted in loss of FMC63 [anti-CD19 CAR] binding to CD19 and complete resistance to [chimeric antigen receptor-engineered T cells targeting CD19] CART19 activity (Figure 1f)…changes to CD19 glycosylation, either enhanced or decreased, impair the ability of CARs to bind and initiate T cell effector function against malignant B cells.”, see page 1721, last five lines of the abstract. These assays utilized acute lymphoblastic leukemia (ALL) cells, see entire abstract.
“Consistent with its known function, loss of SPPL3 resulted in increased addition of complex glycans to CD19. Surface staining of SPPL3KO cells revealed that CD19 antibodies were less capable of binding this hyperglycosylated CD19. This included decreased binding of the antibody used to construct the anti-CD19 CAR (clone FMC63).”, see page 1721.
Heard does not explicitly teach there is a reference biomarker level to compare differences in the glycosylation state of CD19, wherein the assayed malignant B cells had a CD19ΔTyr260 mutation in CD19. Nor, does Heard teach the expression of SPPL3 was determined between a malignant B cell sample and a reference sample.
However, Bot teaches B-cell acute lymphoblastic leukemia resistance to a CAR T cell therapy treatment is associated with the CD19ΔTyr260 mutation in CD19, see Example 10 on page 67. “Additional analysis using flow cytometry showed that CD19 expression was not detected on Jurkat CD19ΔTyr260 cells but was present on Jurkat CD19-WT cells, which suggested that the lack of visualization of cells carrying this point mutation and their resistance to CAR T cell therapy…Fractionated cellular lysates showed WT CD19 in the cell membrane having a high and lower molecular weight band, as well as CD19ΔTyr260 expressed on the surface with a single low molecular weight band. Under deglycosylating conditions, only 1 band was present in both WT CD19 and CD19ΔTyr260 cellular fractions. Without being bound to any scientific theories or hypotheses, it is likely that the CD19ΔTyr260 mutation may result in lack of suitable or functional CD19 glycosylation and/or inhibiting detection. The mutation in B-ALL malignant cells may have potential implications for other anti-CD19 CAR or non-CD19 CAR cell therapy.”, see page 67, section 0372.
And Fischer teaches “[w]ith few exceptions, CD19 expression is high in newly diagnosed B-ALL... Using flow cytometry, we measured CD19 expression levels on a panel of diagnostic samples obtained from patients with DLBCL, mantle cell lymphoma (MCL), follicular lymphoma, and chronic lymphocytic leukemia (CLL). Whereas CLL samples consistently demonstrated CD19 expression levels that approximated those seen on normal B cells, DLBCL, MCL, and follicular lymphoma samples demonstrated significantly lower median CD19 levels, with the greatest interpatient variability observed for DLBCL (Fig. 1A).”, see page 704, 1st column (col.), 1st paragraph (para.).
These differences in CD19 expression between B cell malignancies, DLBCL, MCL, follicular lymphoma and normal B cells cited in Figure 1A are substantial, see page 705; and Figure 1B, Y-axis on page 705. As seen on the Y-axis, the CD19 relative expression is substantially different, see Figure 1A on page 705.
“Primary diagnostic samples of DLBCL, MCL, follicular lymphoma (FL), and CLL were analyzed by flow cytometry for expression of CD19 compared with normal B cells from healthy donors. Shown is CD19 protein expression, relative to healthy donor PBMC B cells on a log2 scale... Statistical differences between groups were analyzed by one-way ANOVA nonparametric test with Dunn post-test correction.”, see Figure 1A caption and the figure on page 705.
It would have been obvious to one of ordinary skill in the art at the
effective filing date of the claimed invention was made to assay the test malignant B cells and reference samples of Fischer for SPPL3 biomarker levels, as well as the glycosylation state of CD19 for biomarker level differences between the two sets of samples, as well as assay for the CD19ΔTyr260 mutation.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in all three references to evaluate, both biomarker levels given all the combination of references teach the requisite assays, which are art known and well established and are routinely performed and easily reproducible. One of ordinary skill in the art would have been motivated to do so
with a reasonable expectation of success by teachings in Bot, the mutation in B-ALL malignant cells may have potential implications for other anti-CD19 CAR or non-CD19 CAR cell therapy.”, see page 67, section 0372.
Moreover, it is art known that CD19 glycosylation and SLLP3 function is inextricably linked, see entire Heard reference, as well as Fisher and Bot.
15. Claim(s) 11-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Heard et al., (Blood 138 (Supplement 1): 1721-1723, 5 November 2021), and further in view of Bondanza et al., WO 2020/020841 A1 (published 30 January 2020), Bot et al., US 2021/0161959 A1 (effectively filed November 6, 2020) and Fischer et al., (J. Immunotherapy 40 (5): 187-195, June 2017). Heard teaches “[g]el-shift analysis demonstrating that loss of SPPL3 results in hyperglycosylation of CD19 while over-expression (SPPL3KO+) results in hypoglycosylation.”, see page 1722, Figure 1e.
“[Heard] confirmed decreased glycosylation of CD19 (Figure 1e), and found that this resulted in loss of FMC63 [anti-CD19 CAR] binding to CD19 and complete resistance to [chimeric antigen receptor-engineered T cells targeting CD19] CART19 activity (Figure 1f)…changes to CD19 glycosylation, either enhanced or decreased, impair the ability of CARs to bind and initiate T cell effector function against malignant B cells.”, see page 1721, last five lines of the abstract. These assays utilized acute lymphoblastic leukemia (ALL) cells, see entire abstract.
“Consistent with its known function, loss of SPPL3 resulted in increased addition of complex glycans to CD19. Surface staining of SPPL3KO cells revealed that CD19 antibodies were less capable of binding this hyperglycosylated CD19. This included decreased binding of the antibody used to construct the anti-CD19 CAR (clone FMC63).”, see page 1721.
Heard does not explicitly teach there is a reference biomarker level to compare differences in the glycosylation state of CD19, wherein the assayed malignant B cells had a CD19ΔTyr260 mutation in CD19. Nor, does Heard teach the expression of SPPL3 was determined between a malignant B cell sample and a reference sample. Nor, does Heard explicitly teach the selection of a B cell malignancy treatment.
However, Heard makes clear “…loss of SPPL3 resulted in increased addition of complex glycans to CD19. Surface staining of SPPL3KO cells revealed that CD19 antibodies were less capable of binding this hyperglycosylated CD19. This included decreased binding of the antibody used to construct the anti-CD19 CAR (clone FMC63). Protein modeling revealed that an asparagine residue known to be normally glycosylated on CD19 (N125) is in close physical proximity to the FMC63 binding site (Figure 1d), suggesting that the addition of complex glycans at this site may be responsible for disruption of CAR binding that led to impaired T cell activation.”, see page 1721, middle of abstract. Hence, after assessment of CD19 glycosylation states, one of ordinary skill in the art would know if there is decreased glycosylation of CD19 the B malignancy is resistant to CART19 activity and another therapy should be selected such as that of Bondanza. Bondanza teaches treating B-cell malignancies comprising solid, haematopoietic or lymphoid tumors with one glycosylation inhibitor in combination with an immunotherapy, preferably a CAR-T cell therapy, see page 1, 1st paragraph (para.); page 3, lines 30 and 31; and page 7, lines 11-21. The CAR T targets CD19, see page 17, lines 23 and 24. With the administration of the disclosed treatment, T cell recognition of CD19 would improve, activation of CAR t cell effector function would increase and CD19-targeted CAR T anti-tumor cytotoxicity would be enhanced.
Bot teaches B-cell acute lymphoblastic leukemia resistance to a CAR T cell therapy treatment is associated with the CD19ΔTyr260 mutation in CD19, see Example 10 on page 67. “Additional analysis using flow cytometry showed that CD19 expression was not detected on Jurkat CD19ΔTyr260 cells but was present on Jurkat CD19-WT cells, which suggested that the lack of visualization of cells carrying this point mutation and their resistance to CAR T cell therapy…Fractionated cellular lysates showed WT CD19 in the cell membrane having a high and lower molecular weight band, as well as CD19ΔTyr260 expressed on the surface with a single low molecular weight band. Under deglycosylating conditions, only 1 band was present in both WT CD19 and CD19ΔTyr260 cellular fractions. Without being bound to any scientific theories or hypotheses, it is likely that the CD19ΔTyr260 mutation may result in lack of suitable or functional CD19 glycosylation and/or inhibiting detection.
And Fischer teaches “[w]ith few exceptions, CD19 expression is high in newly diagnosed B-ALL... Using flow cytometry, we measured CD19 expression levels on a panel of diagnostic samples obtained from patients with DLBCL, mantle cell lymphoma (MCL), follicular lymphoma, and chronic lymphocytic leukemia (CLL). Whereas CLL samples consistently demonstrated CD19 expression levels that approximated those seen on normal B cells, DLBCL, MCL, and follicular lymphoma samples demonstrated significantly lower median CD19 levels, with the greatest interpatient variability observed for DLBCL (Fig. 1A).”, see page 704, 1st column (col.), 1st paragraph (para.).
These differences in CD19 expression between B cell malignancies, DLBCL, MCL, follicular lymphoma and normal B cells cited in Figure 1A are substantial, see page 705; and Figure 1B, Y-axix on page 705. As seen on the Y-axis, the CD19 relative expression is substantially different, see Figure 1A on page 705.
“Primary diagnostic samples of DLBCL, MCL, follicular lymphoma (FL), and CLL were analyzed by flow cytometry for expression of CD19 compared with normal B cells from healthy donors. Shown is CD19 protein expression, relative to healthy donor PBMC B cells on a log2 scale... Statistical differences between groups were analyzed by one-way ANOVA nonparametric test with Dunn post-test correction.”, see Figure 1A caption and the figure on page 705.
It would have been obvious to one of ordinary skill in the art at the
effective filing date of the claimed invention was made to assay the test malignant B cells and reference samples of Fischer for SPPL3 biomarker levels, as well as the glycosylation state of CD19 for biomarker level differences between the two sets of samples to further select treatment for the B cell malignancy. The mutation in B-ALL malignant cells may have potential implications for other anti-CD19 CAR or non-CD19 CAR cell therapy.”, see page 67, section 0372.
One of ordinary skill in the art would have been motivated to do so
with a reasonable expectation of success by teachings in all three references to evaluate, both biomarker levels given all the combination of references teach the requisite assays, which are art known and well established and are routinely performed and easily reproducible. Moreover,
it is art known that CD19 glycosylation and SLLP3 function is inextricably linked, see entire Heard reference, as well as Fisher and Bot.
One of ordinary skill in the art would have been motivated to do so
with a reasonable expectation of success by teachings in all the references, particularly Heard and Bondanza to observe the differences in the levels of biomarkers and select the best therapeutic agent that would has the highest preponderance to yield effective cancer treatment.
Conclusion
16. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
- Ghobadi et al. Discovery of a novel genomic alteration that renders leukemic cells resistant to CD19-targeted immunotherapies. Blood Advances 8(20): 5634-5640, 25 October 2022.
17. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached 8AM-8PM, Monday through Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
26 December 2025
/Alana Harris Dent/Primary Examiner, Art Unit 1643
18165