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.
Status of the Claims
Claims 2, 3, and 12-18 have been canceled by Applicant’s amendment filed 06/11/2026. Claim 1 has been amended. Claims 1 and 4-11 are pending and examined herein.
Priority
This application, filed 09/07/2023, claims benefit of provisional application 63/430,793 filed on 12/07/2022. This priority is acknowledged and the claims examined herein are treated as having an effective filing date of 12/07/2022.
Information Disclosure Statement
The Information Disclosure Statement filed 09/07/2023 is acknowledged and has been considered.
Amended 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 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, and 4-11 are rejected under 35 U.S.C. 103 as being unpatentable over Kam-lung et al. (2019). “Insulin-like growth factor 1 receptor (IGF-1R) expression in peripheral blood mononuclear cells (PBMC) in Thyroid-Associated Orbitopathy (TAO)”. Investigative Ophthalmology & Visual Science, 60(9), 6205-6205. ARVO Annual Meeting Abstract (abstract only, accessed 04/06/2026), (herein referred to as Kam-lung), in view of Douglas et al. (2007). “Aberrant expression of the insulin-like growth factor-1 receptor by T cells from patients with Graves’ disease may carry functional consequences for disease pathogenesis”. The Journal of Immunology, 178(5), 3281-3287, (herein referred to as Douglas), and Smith et al. (2019). “Insulin-like growth factor-I receptor and thyroid-associated ophthalmopathy”. Endocrine reviews, 40(1), 236-267, (herein referred to as Smith).
Regarding claim 1, Kam-lung teaches a method for assessing insulin-like growth factor 1 receptor (IGF-1R) expression status in peripheral blood mononuclear cells (PBMCs) in a patient (abstract - Purpose), comprising the steps of: (i) detecting in a blood sample taken from the patient PBMCs that express IGF-1R; and (ii) determining percentage of PBMCs that express IGF-1R among all PBMCs (abstract – Methods). Kam-lung teaches that euthyroid patients who were referred for recent-onset (<9-month), progressive TAO (n=20) as well as those with GD only (n=20) were recruited for participation in the study (abstract – Methods). Kam-lung teaches that the percentage of IGF-1R positive expression was determined as the population of gated viable cells with increased fluorescent intensity compared with those in isotype control (abstract – Methods). Kam-lung teaches that patients with GD alone show significantly more circulating IGF1R positive PBMC than patients with TAO (99+/-4% vs 65+/-5%, p < 0.01, Mann-Whitney test) (abstract-Results).
However, Kam-lung does not teach determining the percentage from step (ii) to be higher than a standard control value; diagnosing the patient as having thyroid-associated orbitopathy (TAO); and administering to the patient treatment comprising application of lubricant eye drops or nonsteroidal anti-inflammatory drops, administration of steroids, use of prism glasses, orbital decompression, surgery on eyelids or bones around or behind eyes, or cessation of smoking.
Douglas teaches the measurement of IGF-1R expression in PBMCs (T cells) in patients with Graves’ Disease (GD) via flow cytometry (abstract; Fig. 1). Douglas teaches comparing the percentage of T cells expressing IGF-1R in patients with GD with the percentage expressed by control (healthy) patients (abstract; p. 3283, column 1, 5th paragraph; Fig. 1). Douglas found that GD patients expressed significantly more IGF-1R in peripheral T cells compared to control patient T cells (48 ± 5% (mean SE) of T cells from GD patients (n = 33), 15 ± 3% of T cells from control donors (n = 21; p < 108; GD vs controls) (p. 3283, column 1, 5th paragraph; Fig. 1). Furthermore, Douglas also teaches the measurement of IGF-1R expression in T cells derived from orbital tissue and peripheral blood cells of a patient with TAO, and found that the T cells from both tissues from a patient with TAO had a higher percentage of IGF-1R expression than control tissue samples (page 3283, column 2, 1st paragraph; Fig. 2). Douglas also recites that TAO represents the orbital manifestation of GD (page 3281, column 2, 1st full paragraph).
Smith teaches that IGF-1R is overexpressed in several cell types in TAO such as fibrocytes and orbital fibroblasts (“Essential Points” – page 237). Smith also teaches that ~40% of patients with GD present with TAO as a complication, and also that there is a large spectrum of disease characteristics that make a correct and rapid diagnosis difficult (page 237, column 1, 2nd full paragraph). Furthermore, Smith teaches the need for laboratory-based and objective biomarkers of TAO, and that the current scales for grading the severity and activity or stability of the disease are inadequate (page 254, column 1, 1st full paragraph). Smith also teaches that glucocorticoids are, by far, the most frequently used class of drugs in active TAO (page 254, column 1, 2nd full paragraph). Smith also teaches that many reports have appeared over recent decades examining the use of glucocorticoids in active TAO and have attempted to identify the subsets of patients most likely to respond (page 254, column 1, 2nd full paragraph). Smith teaches a study that examined the effects on clinical activity scores (CAS) using three different cumulative dosages of intravenous methylprednisolone (a steroid), administered as 12 weekly infusions, which demonstrated transient benefit, the greatest in the group receiving the highest dosage after a 12-week treatment period (page 254, column 1, 2nd full paragraph). Smith also teaches that better biomarkers for diagnosing TAO are needed, especially those that are objective and laboratory-based, and those that can distinguish TAO from other conditions with orbital manifestations (page 237, column 2, 1st paragraph).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Kam-lung to compare the percentage of PBMCs that express IGF-1R among all PBMCs to a standard control value in patients, as disclosed in Douglas, as it would be “obvious to try” in order to provide a biomarker for the diagnosis of TAO in a patient. While Douglas does not explicitly recite that TAO can be diagnosed when the percentage of PBMCs that express IGF-1R are higher than a standard control value, they establish that T cells derived from orbital tissue and peripheral blood cells had a higher percentage of IGF-1R expression in the samples from the TAO samples than the control tissue samples. Douglas also establishes a correlation between increased PBMC IGF-1R levels and GD, which is often accompanied by a TAO complication. Smith also establishes that several other cell types also have higher IGF-1R levels in TAO patients. The measurement of biomarkers that are known to be correlated with a disease state to diagnose a patient is a well-known, routine, and conventional activity in the art. Therefore, it would be “obvious to try” to use PBMC IGF-1R percentage expression to detect TAO due to established correlation between increased IGF-1R levels in orbital, peripheral T cells, and other cell types of TAO patients relative to control patients, as well as with GD which has significant overlap with TAO.
A skilled artisan would have been motivated to make these modifications because Smith establishes that better biomarkers for diagnosing TAO are needed, especially those that are objective and laboratory-based, and those that can distinguish TAO from other conditions with orbital manifestations (page 237, column 2, 1st paragraph). A person of ordinary skill would have had a reasonable expectation of success in making these modifications to the method of Kam-lung to diagnose TAO by comparing the percentage of PBMCs that express IGF-1R among all PBMCs to a standard control as taught by Douglas because: both Kam-lung and Douglas use flow cytometry methods to measure IGF-1R in PMBCs of TAO patients, and the use of standard control values to compare a biomarker against is a well-known, routine, and conventional activity in the art of disease diagnostics, the incorporation of which simply requires a simple mental or mathematical comparison.
Additionally, it would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Kam-lung to administer a treatment to the patients comprising the administration of steroids, as disclosed in Douglas, as it would be “obvious to try”. Smith teaches that glucocorticoids are by far the most frequently used class of drugs for treating active TAO that have been used for several decades, and the administration of known treatments for patients with disease is an activity that is well-known, routine, and conventional in the art. This established use provides a reasonable expectation of success. A skilled artisan would have been motivated to make this modification to the method of Kam-lung because administering treatments to patients suffering from disease can improve patient outcomes and quality of life metrics.
Regarding claims 4 and 5, Kam-lung also teaches prior to step (i), isolating PBMCs from a blood sample taken from the patient (abstract – Methods).
Regarding claims 6 and 7, Douglas teaches the measurement of IGF-1R expression in PBMCs (T cells) in patients with Graves’ Disease (GD) via flow cytometry (abstract; Fig. 1). Furthermore, Douglas teaches the measurement of IGF-1R by contacting the PBMCs with an anti-IGF-1R antibody that specifically binds IGF-1R (“anti-IGF-1R PE (clone 1H7)”, page 3282, column 1, 1st full paragraph), and that this antibody is conjugated to a detectable label (“fluorochrome conjugated mAbs”, page 3282, column 2, 1st full paragraph).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Kam-lung to use an anti-IGF-1R antibody that specifically binds IGF-1R and is conjugated to a detectable label, as disclosed in Douglas, as it is merely swapping similar features that serve the same purpose. Methods of measurement via flow cytometry generally use either direct or indirect immunofluorescence staining in order to incorporate a label for quantification. A person of ordinary skill would have had a reasonable expectation of success in using an anti-IGF-1R antibody that specifically binds IGF-1R and is conjugated to a detectable label, instead of indirect staining, because using direct immunofluorescence is well known in the art, and Douglas demonstrates that such a primary conjugated antibody exists and has been successfully used. A skilled artisan would have been motivated to make this modification because it would not require a secondary antibody incubation which would save time, and also avoid secondary antibody non-specific binding.
Regarding claim 8, Kam-lung is silent on the specific use of a primary antibody but the use of flow cytometry and recitation of staining with a secondary antibody indicates the use of indirect immunofluorescence staining to quantify IGF-1R. As described above, indirect immunofluorescence staining is the alternative to direct staining. Since Kam-lung already teaches the use of a secondary antibody, it would be “obvious to try” the use of an anti-IGF-1R primary antibody for the secondary to bind to, since Douglas demonstrates the existence of such primary antibodies, that are commercially available, prior to the filing date. A skilled artisan would have been motivated to make this modification because indirect immunofluorescence staining provides lower cost and higher binding sensitivity. A person of ordinary skill would have had a reasonable expectation of success in making this modification to the method of Kam-lung because such primary and secondary antibodies are commercially available and such immunofluorescence techniques in the context of flow cytometry measurement are well-known, routine, and conventional in the art as shown by Kam-lung.
Regarding claim 9, Kam-lung teaches a method for assessing IGF-1R expression status in PBMCs in a sample using flow cytometry (abstract – Methods).
Regarding claims 10 and 11, Kam-lung teaches a method for assessing IGF-1R expression status in PBMCs in a patient sample wherein the patient is a human patient diagnosed with Graves’ Disease (abstract – Purpose, Methods).
Response to Arguments
Applicant's arguments filed 06/11/2026 have been fully considered but they are not persuasive except to the extent expressly indicated below.
Applicant’s arguments on page 4 with respect to the rejection of claims 1-11 under 35 U.S.C. 101 for being directed to a judicial exception and a law of nature without significantly more have been fully considered and are persuasive. Applicant has amended claim 1 to recite the step previously recited in claim 3 plus an added treatment step of "administering to the patient treatment comprising application of lubricant eye drops or nonsteroidal anti-inflammatory drops, administration of steroids, use of prism glasses, orbital decompression, surgery on eyelids or bones around or behind the eyes, or cessation of smoking,". The recited steps in amended claim 1 now integrate the judicial exceptions into a practical application because the claim affirmatively recites particular treatment for patients with thyroid-associated orbitopathy (TAO), and goes beyond merely instructions to “apply” the exception in a generic way. Claims 2-3 have been canceled by Applicant. Accordingly, the rejection of claims 1-11 under 35 U.S.C. 101 has been withdrawn.
Applicant’s arguments on pages 4-5 with respect to the rejection of claims 1, 4, 5, and 9-11 under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Kam-lung et al. (2019). “Insulin-like growth factor 1 receptor (IGF-1R) expression in peripheral blood mononuclear cells (PBMC) in Thyroid-Associated Orbitopathy (TAO)”. Investigative Ophthalmology & Visual Science, 60(9), 6205-6205. ARVO Annual Meeting Abstract (abstract only, accessed 04/06/2026), (herein referred to as Kam-lung), have been fully considered and are persuasive. Applicant has amended claim 1 to additionally recite elements that teach determining the percentage of PBMCs that express IGF-1R among all PBMCs to be higher than a standard control value, and diagnosing the patient as having thyroid- associated orbitopathy (TAO). These teachings are incorporated from cancelled claims 2 and 3 and are not taught by Kam-lung.
Claim 1 and therefore also its dependent claims 4, 5, and 9-11 are no longer anticipated by Kam-lung, the previous rejection of claims 1, 4, 5, and 9-11 under 35 U.S.C. 102(a)(1)/102(a)(2) has been withdrawn. However, Applicant has amended the claims which has necessitated a new ground of rejection under 35 U.S.C. 103 over Kam-lung in view of Douglas et al. (2007). “Aberrant expression of the insulin-like growth factor-1 receptor by T cells from patients with Graves’ disease may carry functional consequences for disease pathogenesis”. The Journal of Immunology, 178(5), 3281-3287, (herein referred to as Douglas), and Smith et al. (2019). “Insulin-like growth factor-I receptor and thyroid-associated ophthalmopathy”. Endocrine reviews, 40(1), 236-267, (herein referred to as Smith).
The rejections of claims 6-8 under 35 U.S.C. 103 are maintained. The rejections have been updated in view of Applicant’s amendments to claim 1.
Applicant argues on pages 5-7 with respect to the rejection of claims 6-8 under 35 U.S.C. 103 that “While Kam-Lung and Douglas both studied the IGF-1R expression status, the two studies focused on different cell types and compared results among different patient populations. As such, the observations reported by Kam-Lung and Douglas at best provide the skilled person a motivation to investigate the IGF-1R expression status of PBMCs in TAO patients for a potential correlation with the condition. But they provide the skilled person no reasonable expectation of success, i.e., that such a correlation indeed exists and therefore would allow him to diagnose TAO based on an increase in the percentage of IGF-R⁺ PBMCs”.
This argument has been fully considered but is not persuasive. As discussed in the rejection above, Douglas establishes a higher percentage of IGF-1R⁺ peripheral blood (T cells) cells and orbital T cells in TAO samples than healthy control samples. Furthermore, this was not a minor difference (TAO - peripheral blood (CD4, 64%; CD3, 61%); Control – peripheral blood (29% and 28%, respectively); TAO - orbital (CD4, 51%; CD3, 56%); Control – orbital (CD4 23%, total CD3 26%). Similar magnitude differences were observed in the comparison between the number of peripheral blood T cells expressing IGF-1R in GD patients versus controls. Additionally, the percentage of peripheral blood (T cells) cells expressing IGF-1R in TAO samples shown in Douglas was very similar to the percentage of PMBC cells expressing IGF-1R in TAO samples shown in Kam-lung (Douglas – (CD4, 64%; CD3, 61%), Kam-Lung – (65+/-5%). The percentage of peripheral blood cells expressing IGF-1R in TAO samples, especially since Douglas also demonstrates the percentage expressed by controls, does in fact provide the skilled person a reasonable expectation of success in using the percentage of IGF-1R expressing peripheral cells to diagnose TAO, considering that in both tissue types the TAO samples expressed double the percentage of IGF-1R⁺ cells. In fact, these levels demonstrated by Kam-lung and Douglas would both theoretically exceed the cutoff value of 32% that can effectively separate healthy and TAO patients, as determined by the specification of the instant application ([0045]). Furthermore, the data shown for the percentage of peripheral blood cells expressing IGF-1R in Kam-lung and Douglas is similar to the data demonstrated in the instant application (Fig. 1B).
Therefore, the argument made by the Applicant on page 7 that “the skilled person would have inadequate basis to extrapolate a correlation between IGF-R⁺ PBMC percentage and TAO (which is needed for the success of the claimed method of this invention) from the correlation between IGF-1R⁺ T cell percentage and TAO (which is reported by Douglas). Scientifically, reasonable predictability is lacking for any such extrapolation”, is not persuasive, as the high percentage of IGF-1R⁺ cells in TAO samples shown by both Kam-lung and Douglas would provide adequate basis for one of ordinary skill in the art use PMBC IGF-1R expression levels to diagnose TAO.
Applicant further argues that “Specifically, Kam-Lung reports a higher percentage of IGF-R⁺ PBMCs in GD patients than in TAO patients (99% V. 66%) and suggests that GD patients may be monitored using IGF-R⁺ PBMCs as a surrogate biomarker for indicating their risk of developing TAO. Conversely, Douglas reports a higher percentage of IGF-1R⁺ T cells in GD patients than healthy control subjects (48% V. 15%, see the abstract) and a higher percentage of IGF-1R⁺ T cells in TAO patients than healthy control subjects (51-64% V. 23-29%, see the 1st paragraph of right column on page 3283). Thus, the skilled person reading both Kam-Lung and Douglas would recognize that two different cell types were studied: PBMCs in Kam-Lung and T cells in Douglas”.
This argument has been fully considered but is not persuasive. Claim 1 recites the use of “peripheral blood mononuclear cells (PBMCs)”. As defined in the instant application specification ([0012]), and reiterated by the Applicant on page 7 of the arguments, T cells are considered PBMCs. Therefore, Douglas does in fact teach the use of PBMCs in their method. Additionally, and regardless, the rejection does not rely on the teachings of Douglas alone to teach the entire claimed method, and the method of Kam-lung specifically recites the use of PBMCs. In light of these facts, asserting that the combination of Kam-lung, Douglas, and Smith would not be obvious because Kam-lung and Douglas studied “two different cell types” would also be to attack the references individually. Whether directly stated or not by the Applicant, arguing that there would not be a reasonable expectation of success in combining Kam-lung and Douglas because they teach “two different cell types”, would be akin to attacking the teachings of Douglass individually, when the rejection is based on a combination 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). The rejection does not rely on Douglas alone to teach the entire claimed method, and regardless as discussed above, Douglass does teach the use of PMBCs as recited in the instantly claimed specification. Rather, the rejection relies on the combined teachings of Kam-lung, Douglas, and Smith to establish that the claimed method would have been obvious to one of ordinary skill in the art, and as discussed above, their teachings also provide sufficient evidence to have a reasonable expectation of success in making the combination.
Applicant also argues on page 7 that “Predictability in making such extrapolation is further diminished by the fact that Kam-Lung found a much higher percentage of IGF-R⁺ PBMCs in GD patients than in TAO patients (99% V. 66%), whereas Douglas found the percentage of IGF-1R⁺ T cells in GD patients to be comparable to or moderately lower than in TAO patients (48% V. 51-64%). This inconsistency would convey to the skilled person that the percentages of IGF-R⁺ PBMCs and IGF-R⁺ T cells among GD or TAO patients do not directly correspond with each other in a straightforward or linear fashion; rather, the skilled person would realize the correlation (if one does exist) would most certainly to be more complex and unpredictable. This unpredictability negates any and all reasonable expectation of success for the skilled person to arrive at the claimed method of this invention by combining the teaching of Kam-Lung and Douglas”.
This argument has been fully considered but is not persuasive. First, the focus made on the comparisons between levels in GD and TAO by the Applicant are irrelevant. Claim 1 does not recite GD, nor does the method taught by any of the claims focus on differentiating between TAO and GD, therefore citing the variation in the percentage of IGF-R⁺ expressing cells between Kam-lung and Douglas is irrelevant. Second, one of ordinary skill in the art would understand that variation is always present when comparing a measured variable across two different studies, especially when using two entirely different patient populations. Applicant cites that this unpredictability negates any and all reasonable expectation of success, however, the unpredictability is not present with regards to the actual subject matter being claimed (diagnosis of TAO). As discussed above, the percentage of peripheral blood (T cells) cells expressing IGF-1R in TAO samples shown in Douglas was very similar to the percentage of PMBC cells expressing IGF-1R in TAO samples shown in Kam-lung (Douglas – (CD4, 64%; CD3, 61%), Kam-Lung – (65+/-5%). AS the claims are focused on diagnosing TAO and not GD, this is a far more compelling comparison and a strong indicator of a reasonable expectation of success for the skilled person to arrive at the claimed method of the instant invention by combining the teaching of Kam-Lung, Douglas, and Smith.
Therefore, due to the reasons above, the Applicant’s arguments that the Office has not established a prima facie case of obviousness due to failure to establish a reasonable expectation of success are not persuasive and the rejection of claims 6-8 under 35 U.S.C. 103 are maintained. Applicant has amended claims 1 which has necessitated a modification to the rejections. Claims 1 and 4-11 are now rejected under 35 U.S.C. 103 as being unpatentable over Kam-lung in view of Douglas and Smith (see above rejections).
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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.
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/ALEXANDER J. HOFFMAN/
Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 August 26, 2026
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