Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amendment filed February 26, 2026 in response to the Office Action of November 26, 2026 is acknowledged and has been entered.
Claims 1, 3, and 7 have been amended.
Claims 2, and 19-22 have been cancelled.
Claims 1, 3-15, and 17 are pending.
Claims 6 and 10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1, 3-5, 7-9, 11-15, and 17 are currently under consideration as drawn to the elected invention.
In view of cancellation of claim 22, the priority date has been established as January 31, 2020 for all claims under examination.
In view of the specification amendments, the objection to color drawings set forth in the Office Action of November 26, 2026 is hereby withdrawn.
In view of cancellation of claims 2 and 22 and amendments of claims 3 and 7, the claim objections set forth in the Office Action of November 26, 2026 is hereby withdrawn.
In view of cancellation of claims 2 and 22, the 112(b) rejections set forth in the Office Action of November 26, 2026 is hereby withdrawn.
In view of cancellation of claim 22, the 101 rejections set forth in the Office Action of November 26, 2026 is hereby withdrawn.
MAINTAINED/MODIFIED REJECTIONS
Claim Rejections - 35 USC § 112(a)
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, 3-5, 7-9, 11-15, and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is drawn to a method of diagnosing and treating uveal melanoma in a patient, the method comprising: a) obtaining a vitreous sample from an eye of the patient; b) measuring levels of expression of sialic acid-binding Ig-like lectin 6 (SIGL6), Myc proto-oncogene protein (MYC), oncostatin-M (OSM), stem cell growth factor receptor Kit (SCFR/KIT), fatty acid-binding protein 1 (FABP1), granulocyte-macrophage colony-stimulating factor receptor (GM-CSF Ra), and kallikrein 7 (KLK7); c) determining that the subject has increased levels of expression of SIGL6, MYC,OSM, and SCFR/KIT and decreased levels of expression of FABP1, GM-CSF Ra, and KLK7 compared to reference value ranges for the levels of expression of the biomarkers in a vitreous sample from a control subject, wherein the increased levels of expression of the SIGL6, MYC, OSM, and SCFR/KIT and the decreased levels of expression of the FABP1, GM-CSF Ra, and KLK7 indicate that the patient has uveal melanoma; and d) treating the patient diagnosed with the uveal melanoma with a treatment for the uveal melanoma. As evidenced by claims 3-5 and 7-9, the claims further encompass a broad genus of one or more biomarkers from more than 140 genes for GEP classification; and a broad genus of one or more biomarkers form more than 70 genes for PRAME classification. Thus, the claims encompass a seven-gene combination for diagnosis of uveal melanoma, a broad genus of gene selections for classifying GEP class, and/or a broad genus of gene selections for classifying PRAME status. Just considering classifying GEP class (dependent claim 3), selections of one or more biomarkers from about 140 genes would include enormous number of combinations (~2140). Given that the expression levels can be increased, decreased or no change, the possible comparison outcomes can be even more complicated.
Examples of the specification described proteomic data based on very limited samples from eight uveal melanoma patients and three controls. Based on the proteomic data, specification identified several potential biomarkers whose expressions are associated with uveal melanoma in the training data set. Since the study analyzed a limited number of samples, additional studies are necessary to validate these findings. However, the specification does not verify any of the genes in real diagnosis setting, or in classification GEP class or in classification PRAME status. It is unclear what is the sensitivity or specificity of the claimed method using the one or more biomarker(s) encompassed by the claims. Thus, the specification does not provide sufficient written description support for the claimed method.
Vas-Gath, Inc. v" Mahurkar, 19 USPQ2d 1111, makes clear that "to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed".
Regarding the seven-gene combination for diagnosing uveal melanoma, even the instant specification acknowledges: “The limited number of samples and high number of measurements can introduce bias and false positives in the training set.” (see paragraph [0211] of the instant publication US 2023/0152322). The specification just has a general description about the validation design (paragraph [0211] and Fig. 6), the performance of the biomarkers in the validation study is not fully disclosed. Skeie (Skeie et al., PLOS ONE 10(5): e0127567, Publication Date: 05/28/2015, of record) teaches vitreous is a complex extracellular tissue where proteins originated from local hyalocyte and tissues, some of which are local and others are outside of the eye. The vitreous proteome become drastically altered as a results of systemic disease. In addition, All-Ericsson (US 2006/0111363 A1, Publication Date: 05/25/2006, cited in IDS of 11/09/2022, of record) shows that gene expression can vary significantly even among uveal melanoma samples. For example, among 134 uveal melanoma samples, 50 have no c-Kit positive cells, 18 have < 10% c-Kit positive cells, 18 have 10%-50% c-Kit positive cells, and 48 have >50% c-Kit positive cells (Example 2, [0032]). It is noted that c-Kit is one of the biomarkers encompassed by the elected combination. Thus, the biomarkers, which are identified based on limited number of vitreous samples, may be false positives or false negatives in diagnosing uveal melanoma.
Consistent with this complexity, Velez (Velez et al., Molecular Cancer, 2021, 20:39 including suppl., Publication Year: 2021, of record. It is noted that the inventors of the instant application is also the co-author of the article. In addition, the training dataset in the article appears the same as the dataset described in the instant application) shows that the performance of the biomarkers in the validation dataset (including 20 uveal melanoma samples) is neither consistent nor predictable. For example, only 6 out of 20 biomarkers shows significant expression between control and uveal melanoma samples based on verification expression data (see Table S7). Even for the biomarkers in the seven-gene combination, the biomarker expression patterns change significantly between the training data set and the validation dataset. For example, in the training dataset, FABP1 protein level is significantly decreased in uveal melanoma samples (Fig 5A of the instant specification; and Fig. S1A of Velez). However, in the verification study, FABP1 protein levels are higher in uveal melanoma samples (Fig. S2A of Velez). Similarly, in the training dataset, the GM-CSF Ra protein level is significantly decreased in uveal melanoma samples (Fig 5B of the instant specification; and Fig. S1B of Velez). However, in the verification study, GM-CSF Ra protein levels are higher in uveal melanoma samples (Fig. S2A of Velez). In addition, in the training dataset, the c-MYC protein level is higher in uveal melanoma samples (Fig 5E of the instant specification; and Fig. S1E of Velez). However, in the verification study, C-MYC protein levels are similar between control and uveal melanoma samples. Based on the data in the specification and Velez, the one or more biomarkers encompassed by claim 1 do not show consistent expression patterns associated with uveal melanoma.
Additionally, the amended claim 1 indicates that decreased levels of expression of FABP1, GM-CSF Ra, and KLK7 compared to a control would be associated with a positive diagnosis for uveal melanoma. However, based on the verification data, increased levels of expression of FABP1 and GM-CSF Ra compared to a control appears to be associated with a positive diagnosis for uveal melanoma (see Fig. S2A of Velez).
Taken together, limited disclosed data in the specification would not be sufficient to establish a reliable association between the expression levels of the seven-gene combination of the amended claim and a positive diagnosis of uveal melanoma as claimed.
Furthermore, claims 3-5 recite a broad genus of one or more biomarkers for GEP classification. As indicated by the instant specification, the training dataset only comprises three GEP class 2 uveal melanoma and five GEP class 1 uveal melanoma (see paragraphs [0195]-[0202] of the instant publication US 2023/0152322 A1). Thus, the data for differentiating GEP classes is even more limited. In addition, the specification does not validate any of the one or more biomarkers encompassed by claims 3-5 in GEP classification, even for the elected combination: OSM, CSF2RB, GM-CSF Ra, FABP1, KLK7, OMgp, SIR1, siglec-6, MEF2C, arginase-1, DNMT3A and HB-EGF. In fact, the biomarker expression patterns change significantly between the training data set and the validation dataset. For examples, OSM, sirtuin 1, MEF2C, arginase-1, DNMT3A shows significant different expression levels between class 1 and class 2 in the training dataset (based on p-value Class 2 vs. Class 1, see Table 3 of the instant publication US 2023/0152322 A1). However, none of these biomarkers show significant different expression levels between class 1 and class 2 in the verification dataset (see Fig. S2C and Fig. S2D). Thus, the inconsistent results disclosed in the specification and Velez show that the performance of the one or more biomarkers encompassed by claims 3-5 are not consistent or reliable in classifying GEP classes of uveal melanoma.
Furthermore, claims 7-9 recite a broad genus of one or more biomarkers for PRAME classification. As indicated by the instant specification, the training dataset only comprises four PRAME positive uveal melanoma and four PRAME negative uveal melanoma (see paragraphs [0195]-[0202] of the instant publication US 2023/0152322 A1). Thus, the data for differentiate PRAME classes is even more limited. In addition, the specification does not validate any of the one or more biomarkers encompassed by claims 7-9 in PRAME classification. GM-CSF Ra, FABP1, KLK7 and siglec-6 (the biomarkers in the elected combination) show similar expression levels between PRAME positive and PRAME negative uveal melanoma samples (based on p-value positive vs. negative, see Table 4 of the instant publication US 2023/0152322 A1; and Fig. S3 of Velez). Desmoglein-3 shows significant different expression levels between PRAME positive and PRAME negative in the training dataset (based on p-value positive vs. negative of Table 4; and Fig. 5O of the instant publication US 2023/0152322 A1). However, the expression difference for desmoglein-3 is not statistically-significant in the verification dataset (Fig. S3C of Velez). Taken together, these results show that the performance of the one or more biomarkers encompassed by claims 7-9 are not consistent or reliable in classifying PRAME status of uveal melanoma.
Taken together, the limited disclosed data in the specification would not be sufficient to establish a reliable association between the expression of the encompassed biomarkers and diagnosis/classification of uveal melanoma status as claimed. Thus, the specification lacks written description support for the claimed method.
Claims 11-15 and 17 encompass the same genus of biomarker selections as claim 1 which lacks written description support as set forth above. Thus, the specification fails to provide sufficient written description support for these claims.
Response to Arguments
For the WRITTEN DESCRIPTION rejection of claims 1, 3-5, 7-9, 11-15, and 17 under 35 U.S.C. 112(a), Applicant argues:
As amended, independent claim 1 specifies that levels of expression of sialic acid-binding lg-like lectin 6 (SIGL6), Myc proto-oncogene protein (MYC), oncostatin-M (OSM), stem cell growth factor receptor Kit (SCFR/KIT), fatty acid-binding protein 1 (FABP1), granulocyte-macrophage colony stimulating factor receptor (GM-CSF Ra), and kallikrein 7 (KLK7) are measured in the vitreous sample and that increased levels of expression of the SIGL6, MYC, OSM, and SCFR/KIT and decreased levels of expression of the FABP1, GM-CSF Ra, and KLK7 indicate that the patient has uveal melanoma. Therefore, independent claim 1, as amended, does not encompass a broad genus of more than a million combinations and does specify which biomarkers have their expression levels increased or decreased to allow a determination that a patient has uveal melanoma.
Applicant’s arguments have been considered, but have not been found persuasive. As set forth above, the amended claim 1 still encompass a vast number of gene combination for classifying GEP class and classifying PRAME status. The specification fails to provide sufficient written description support for the broadly claimed method as set forth above. In addition, even though the amended claim 1 cites a specific 7-gene combination at the diagnosing step, the specification has not established the measured 7-gene markers/data correlates with the uveal melanoma. As set forth above, the 7-marker genes were identified through very limited data set and performance of these marker genes were not validated. The data in the prior art (including the results from the inventor’s group) demonstrated that these genes can’t reliably diagnose uveal melanoma. Based on the data in the instant specification and prior art, would not allow a person of ordinary skill in the art to recognize that the inventor possessed the claimed diagnostic steps and correlations.
The specification further describes how the biomarkers were identified based on their differential expression in 8 uveal melanoma patients compared to controls (see specification, e.g., at paragraphs [00150]-[00153] and FIGS. 3A, 3B, 4A, 4B, and 5). Applicant acknowledges that the expression levels of the biomarkers have been found to vary in patients having uveal melanoma depending on the disease subtype, severity, or stage of disease, for example, as identified by gene expression profile (GEP) class or preferentially expressed antigen in melanoma (PRAME) status (see specification, e.g., at paragraphs [00156] and Table 3, Table 4, Table 6, and Table 7). However, Applicant respectfully submits that in spite of patient heterogeneity, the claimed biomarkers have been identified as useful in detecting uveal melanoma in some patients.
Applicant’s arguments have been considered, but have not been found persuasive. As set forth above, the data in the specification were based on very limited patient population (8 uveal melanoma patients and 3 controls). And the biomarkers identified have not been validated by other independent populations. In addition, prior art from inventor’s group (see Velez) shows that the claimed biomarkers cannot be validated in a larger population study. Thus, the specification would not be sufficient to establish a reliable association between the expression levels of the seven-gene combination of the amended claim and a positive diagnosis of uveal melanoma as claimed; the inconsistent results disclosed in the specification and prior art (in particular Velez) show that the performance of the one or more biomarkers encompassed by claims 3-5 are not consistent or reliable in classifying GEP classes of uveal melanoma; and the performance of the one or more biomarkers encompassed by claims 7-9 are not consistent or reliable in classifying PRAME status of uveal melanoma.
Thus, the rejection is maintained for the reasons of record.
Claims 1, 3-5, 7-9, 11-15, and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Examples of the specification described proteomic data based on very limited samples from eight uveal melanoma patients and three controls. Based on the proteomic data, specification identified several potential biomarkers whose expressions are associated with uveal melanoma in the training data set. However, the specification does not verify any of the genes in real diagnosis setting, or in classification GEP class or in classification PRAME status. Thus, the performance of these biomarkers in evaluating/classifying uveal melanoma status is unpredictable and unreliable.To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir.,1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention 5) the state of the art, 6) the relative skill of those in the art, 7) the predictability of the art and 8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108,427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Nature of invention and breadth of the claims:
Claim 1 is drawn to a method of diagnosing and treating uveal melanoma in a patient, the method comprising: a) obtaining a vitreous sample from an eye of the patient; b) measuring levels of expression of sialic acid-binding Ig-like lectin 6 (SIGL6), Myc proto-oncogene protein (MYC), oncostatin-M (OSM), stem cell growth factor receptor Kit (SCFR/KIT), fatty acid-binding protein 1 (FABP1),granulocyte-macrophage colony-stimulating factor receptor (GM-CSF Ra), and kallikrein 7 (KLK7); c) determining that the subject has increased levels of expression of SIGL6, MYC,OSM, and SCFR/KIT and decreased levels of expression of FABP1, GM-CSF Ra, and KLK7 compared to reference value ranges for the levels of expression of the biomarkers in a vitreous sample from a control subject, wherein the increased levels of expression of the SIGL6, MYC, OSM, and SCFR/KIT and the decreased levels of expression of the FABP1, GM-CSF Ra, and KLK7 indicate that the patient has uveal melanoma; and d) treating the patient diagnosed with the uveal melanoma with a treatment for the uveal melanoma. As evidenced by claims 3-5 and 7-9, the claims further encompass a broad genus of one or more biomarkers from more than 140 genes for GEP classification; and a broad genus of one or more biomarkers form more than 70 genes for PRAME classification. Thus, the claims encompass a seven-gene combination for diagnosis of uveal melanoma, a broad genus of gene selections for classifying GEP class, and/or a broad genus of gene selections for classifying PRAME status. Just considering classifying GEP class (dependent claim 3), selections of one or more biomarkers from about 140 genes would include enormous number of combinations (~2140). Given that the expression levels can be increased, decreased or no change, the possible comparison outcomes can be even more complicated.
Relative skill in the art:
The relative skill of those in the art is high with an MD or a PhD.
Level of unpredictability in the art and State of the prior art:
Regarding the one or more biomarkers for uveal melanoma diagnosis, even the instant specification acknowledges: “The limited number of samples and high number of measurements can introduce bias and false positives in the training set.” (see paragraph [0211] of the instant publication US 2023/0152322). However, the performance of the biomarkers in the validation data set is not fully disclosed, other than the general description in paragraph [0211] and Fig. 6. Skeie (Skeie et al., PLOS ONE 10(5): e0127567, Publication Date: 05/28/2015, of record) teaches vitreous is a complex extracellular tissue where proteins originated from local hyalocyte and tissues, some of which are local and others are outside of the eye. The vitreous proteome become drastically altered as a results of systemic disease. All-Ericsson (US 2006/0111363 A1, cited in IDS of 11/09/2022, of record) shows that gene expression can vary significantly even among uveal melanoma samples. For example, among 134 uveal melanoma, 50 have no c-Kit positive cells, 18 have < 10% c-Kit positive cells, 18 have 10%-50% c-Kit positive cells, and 48 have >50% c-Kit positive cells (Example 2, [0032]) (It is noted that c-Kit is one of the biomarkers encompassed by the instant claims). Thus, the biomarkers, which are identified based on limited number of vitreous samples, may be false positives or false negatives in diagnosing uveal melanoma.
Consistent with this complexity, Velez (Velez et al., Molecular Cancer, 2021, 20:39, of record. It is noted that the inventors of the instant application is also the co-author of the article. In addition, the training dataset in the article appears the same as the dataset described in the instant application) shows that the performance of the biomarkers in the validation dataset (including 20 uveal melanoma samples) is neither consistent nor predictable. For example, only 6 out of 20 biomarkers shows significant expression between control and uveal melanoma samples based on verification expression data (see Table S7). Even for the biomarkers in the seven-gene combination, the biomarker expression patterns change significantly between the training data set and the validation dataset. For example, in the training dataset, FABP1 protein level is significantly decreased in uveal melanoma samples (Fig 5A of the instant specification; and Fig. S1A of Velez). However, in the verification study, FABP1 protein levels are higher in uveal melanoma samples (Fig. S2A of Velez). Similarly, in the training dataset, the GM-CSF Ra protein level is significantly decreased in uveal melanoma samples (Fig 5B of the instant specification; and Fig. S1B of Velez). However, in the verification study, GM-CSF Ra protein levels are higher in uveal melanoma samples (Fig. S2A of Velez). In addition, in the training dataset, the c-MYC protein level is higher in uveal melanoma samples (Fig 5E of the instant specification; and Fig. S1E of Velez). However, in the verification study, C-MYC protein levels are similar between control and uveal melanoma samples. Based on the data in the specification and Velez, the biomarkers encompassed by claim 1 do not show consistent expression patterns associated with uveal melanoma.
Claims 3-5 further recite a broad genus of one or more biomarkers for GEP classification. As indicated by the instant specification, the training dataset only comprises three GEP class 2 uveal melanoma and five GEP class 1 uveal melanoma (see paragraphs [0195]-[0202] of the instant publication US 2023/0152322 A1). Thus, the data for differentiating GEP classes is even more limited. In addition, the specification does not validate any of the one or more biomarkers encompassed by claims 3-5 in GEP classification. Even for the biomarkers in the elected combination, the biomarker expression patterns change significantly between the training data set and the validation dataset. For examples, OSM, sirtuin 1, MEF2C, arginase-1, DNMT3A shows significant different expression levels between class 1 and class 2 in the training dataset (based on p-value Class 2 vs. Class 1, see Table 3 of the instant publication US 2023/ 0152322 A1). However, none of these biomarkers show significant different expression levels between class 1 and class 2 in the verification dataset (see Fig. S2C and Fig. S2D). Again, this shows that the performance of the one or more biomarkers encompassed by claims 3-5 is not consistent or reliable in classifying GEP classes of uveal melanoma.
Claims 7-9 further recite a broad genus of one or more biomarkers for PRAME classification. As indicated by the instant specification, the training dataset only comprises four PRAME positive uveal melanoma and four PRAME negative uveal melanoma (see paragraphs [0195]-[0202] of the instant publication US 2023/0152322 A1). Thus, the data for differentiating PRAME classes is even more limited. In addition, the specification does not validate any of the one or more biomarkers encompassed by claims 7-9 in PRAME classification. Based on the training dataset, GM-CSF Ra, FABP1, KLK7 and siglec-6 show similar expression levels between PRAME positive and PRAME negative uveal melanoma samples (see p-value positive vs. negative, in Table 4 of the instant publication US 2023/0152322 A1; and Fig. S3 of Velez). Desmoglein-3 shows significant different expression levels between PRAME positive and PRAME negative in the training dataset (see p-value positive vs. negative in Table 4; and Fig. 5O of the instant publication US 2023/0152322 A1). However, the expression difference for desmoglein-3 is not statistically-significant in the verification dataset (Fig. S3C of Velez). Again this shows that the performance of the one or more biomarkers encompassed by claims 7-9 is not consistent or reliable in classifying PRAME status of uveal melanoma.
Thus, the performance of these biomarkers in evaluating/classifying uveal melanoma status is unpredictable and unreliable.
Direction or guidance and working examples:
MPEP § 608.01 (p) provided that within the specification, "specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims.
However, in view of above, the specification does not provide adequate direction or guidance for the claimed methods. As set forth above, Examples of the instant specification disclosed a few potential biomarkers in vitreous samples based on very limited proteomic data. The performance of these biomarkers were not validated. The claimed methods have not been evaluated (e.g. specificity and or sensitivity). Based on the data of Velez, the associations between expression levels of the claimed biomarkers and uveal melanoma, GEP classification, PRAME status classification, or uveal melanoma condition can not be established. Based on the data disclosed in the instant specification and Velez, one of ordinary skilled in the art would not be able to confidently diagnose a uveal melanoma based on the expression levels of the claimed biomarkers (e.g. a combination of SIGL6, c-MYC, OSM, SCFR/c-Kit, FABP1, GM-CSF Ra, and KLK7); would not be able to confidently classify GEP class based on the expression levels of the claimed biomarkers (e.g. a combination of OSM, CSF2RB, GM-CSF Ra, FABP1, KLK7, OMgp, SIR1, siglec-6, MEF2C, arginase-1, DNMT3A and HB-EGF); would not be able to confidently classify PRAME status based on the expression levels of the claimed biomarkers (e.g. a combination of DSG3, GM-CSF Ra, FABP1, KLK7 and siglec-6).
The quantity of experimentation needed:
The factors outlined in In Re Wands' mentioned above apply here, and in particular as per the MPEP 2164.01 (a): "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." It is very clear that one could not make/use this very broad invention that has no working examples in this unpredictable art without undue experimentation. Genetech Inc vs Nova Nordisk 42 USPQ 2d 1001 "A patent is not a hunting license. It is not a reward for search but compensation for its successful conclusion and patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable."
Applicant is reminded that MPEP 2164.03 teaches “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 428 F.2d 833, 166 USPQ 18, 24 (CCPA 1970) the amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly state in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order for it to be enabling. Given only lack of guidance in the specification and prior art, no one skilled in the art would accept the assertion that the claimed invention would function as contemplated or as claimed based only on the information in the specification and prior art and that known in the art at the time the invention was made.
The specification and prior art provide insufficient guidance with regard to these issues and provides sufficient working examples which would provide guidance to one skilled in the art and no evidence has been provided which would allow one of skill in the art to predict that the invention will function as contemplated or claimed with a reasonable expectation of success. For the above reasons, it appears that undue experimentation would be required to practice the claimed invention.
Response to Arguments
For the Enablement rejection of claims 1, 3-5, 7-9, 11-15, and 17 under 35 U.S.C. 112(a), Applicant argues:
The independent claim 1, as amended, does not encompass a broad genus of more than a million combinations and does specify which biomarkers have their expression levels increased or decreased to allow a determination that a patient has uveal melanoma.
The specification describes how to measure levels of biomarkers in a vitreous sample (see specification, e.g., at paragraphs [0074]-[0076], [00114]- 00122], and [00163]-[00165]) and how vitreous samples can be obtained from a patient (see specification, e.g., at paragraphs [0064], [0093], and [00162]). The specification further describes how the biomarkers were identified based on their differential expression in 8 uveal melanoma patients compared to controls (see specification, e.g., at paragraphs [00150]-[00153] and FIGS. 3A, 3B, 4A, 4B, and 5). Applicant acknowledges that the expression levels of the biomarkers have been found to vary in patients having uveal melanoma depending on the disease subtype, severity, or stage of disease, for example, as identified by gene expression profile (GEP) class or preferentially expressed antigen in melanoma (PRAME) status (see specification, e.g., at paragraphs [00156] and Table 3, Table 4, Table 6, and Table 7).
Applicant’s arguments have been considered, but have not been found persuasive. Applicant reiterate similar arguments which are used above. As set forth above, the amended claim 1 still encompass a vast number of gene combination for classifying GEP class and classifying PRAME status. Additionally, the data in the specification were based on very limited patient population (8 uveal melanoma patients and 3 controls). And the biomarkers identified have not been validated by other independent populations. In addition, prior art from inventor’s group shows that the claimed biomarkers cannot be validated in a larger population study (11 uveal melanoma patients and 11 controls in validation study of Velez, 2021). Thus, the specification would not be sufficient to establish a reliable association between the expression levels of the seven-gene combination of the amended claim and a positive diagnosis of uveal melanoma as claimed; the inconsistent results disclosed in the specification and Velez show that the performance of the one or more biomarkers encompassed by claims 3-5 are not consistent or reliable in classifying GEP classes of uveal melanoma; and the performance of the one or more biomarkers encompassed by claims 7-9 are not consistent or reliable in classifying PRAME status of uveal melanoma.
Thus, the rejection is maintained for the reasons of record.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHENG LU/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642
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