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 .
Status of claims
Claims 1, 5-7, 9 and 11 as amended and new claims 15-18 as filed on 10/07/2025 are under examination in the instant office action.
Claim Objections
Claim 1 as amended is objected to because of the following informalities:
Claim 1 as amended recites specific markers. But it appears that there are some typing errors or ghosts from original disclosure referring to a specific cited reference number; for example: (18,19) and (20). Presence of coma in recitation “HLA-DRB3*0301.(20)” is unclear. Presence of coma in the middle of the claim is not appropriate.
Appropriate clarifications and/or corrections are required.
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.
Claims 1, 5-7, 9 and 11 as amended and new claims 15-17 remain/are rejected under 35 U.S.C. 103 as being unpatentable over US 2016/0281165 (Goldring et al), Vasudevan et al (“Cellular Response to Prosthetic Wear Debris Differs in Patients With and Without Rheumatoid Arthritis”. Arthritis and rheumatism. April 2012, Vol. 64, pages 1005-1014) and Fejzic et al (“Crosslinks Between Human Leukocyte Antigen DRB1*01 and Human Leukocyte Antigen DRB1*13 Allelic Variants and Occurrence of Rheumatoid Arthritis in Patients From Federation of Bosnia and Herzegovina”. Arch Rheumatology. 2017, 32(4), pages 290-297).
US 2016/0281165 (Goldring et al) discloses a method of screening a subject for conditions associated with reaction to implant-derived debris such as adverse local tissue reaction (ALTR), adverse response to metal debris (ARMD) or aseptic lymphocyte dominated vasculitis associated lesion (ALVAL); for example: see abstract and see page 1, par. 0007.
In particular, the cited method comprises steps of:
1) contacting in vitro a subject's biological sample with means to detect is a marker associated with adverse response (for example: see par. 0014);
2) determining whether the subject has the marker (for example: see par. 0014); and
3) treating the subject with a therapeutic agent to ameliorate an adverse response (see par. 0017, for example).
In the cited method the marker associated with ARMD or ALTR include some HLA genotype associated with an immune response or an immune inflammatory condition including HLA-DQA1, HLA-DQA2 (see page 19, table 4, lines 3).
The cited US 2016/0281165 (Goldring et al) is silent about detecting specific claim-recited markers of ARMD or ALTR as result of immune response to implant materials in specific subset of patients with rheumatoid arthritis affected by ARMD or ALTR.
It is well known in the art that rheumatoid arthritis (RA) is strongly associated with predisposition to ARMD or ALTR. For example: the reference by Vasudevan explicitly teaches that patients with RA exhibit a distinct cellular response to implant wear (thereby, ARMD or ALTR) as compared with patients without RA (see abstract at conclusion).
The prior art also teaches HLA markers associated with inflammatory condition such as rheumatoid arthritis. For example: the reference by Fejzic discloses and clearly teaches the specific markers HLA-DRB1*01, HLA- DRB1*04 and HLA-DRB1*10 as being the markers of rheumatoid arthritis (see abstract 291, col.1, par. 2, lines 9-11).
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to select for screening the specific HLA markers such as HLA-DRB1*01, HLA- DRB1*04 and HLA-DRB1*10 as HLA markers in the method of US 2016/0281165 (Goldring et al) for screening a subject to determine the likelihood of adverse local tissue reaction (ALTR), adverse response to metal debris (ARMD) or ALVAL which is based on detection of HLA markers with a reasonable expectation of success in determining a predisposition to ALTR, ARMD or ALAVAL of a subject receiving implant because a predisposition to ARMD, ALTR or ALVAL is strongly linked/associated with inflammatory condition that is rheumatoid arthritis (RA) and because the RA markers are HLA-DRB1*01, HLA- DRB1*04 and HLA-DRB1*10.
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Further, as applied to claims 5-7: in the method of US 2016/0281165 (Goldring et al) the subject's biological samples include any tissue, cells or liquid near implant including blood (par. 0123-1265).
As applied to claim 9: in the method of US 2016/0281165 (Goldring et al) the subjects have aseptic lymphocyte dominated vasculitis associated lesion (ALVAL); for example: see page 1, par. 0007.
As applied to claim 11: in the method of US 2016/0281165 (Goldring et al) the biological sample is obtained from the subject prior to, during, and/or after the subject has had an implant procedure (par. 0115).
As applied to claim 15: in the method of US 2016/0281165 (Goldring et al) the subject are administered a treatment for ALTR or ARMD upon detection of specific markers or genes (see par. 0017, for example).
With regard to claims 16-17: the cited 2016/0281165 (Goldring et al) teaches and/or suggests that the treatment for ALTR or ARMD comprises modulating immune response by administering agents that decrease, block expression of the detected gene markers, bind/target specific subtypes of ALTR, and, thus, implant failure can be prevented (par. 0184). The cited 2016/0281165 (Goldring et al) acknowledges that up-regulates genes in ALTR include Human Leukocyte Antigen DQ proteins; for example: HLA-DQA2 and HLA-DQA1 (see table 4 at col. 19). Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to select a compound that bids to Human Leukocyte Antigen DQ proteins in order to modulate MHC mediated immune response (same as HLA-mediated response in humans) since the Human Leukocyte Antigen DQ proteins (HLA-DQA2 and HLA-DQA1) are upregulated in human subjects having ALTR.
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Claims 1, 5-7, 9, 11 and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over US 2016/0281165 (Goldring et al), Vasudevan et al (“Cellular Response to Prosthetic Wear Debris Differs in Patients With and Without Rheumatoid Arthritis”. Arthritis and rheumatism. April 2012, Vol. 64, pages 1005-1014) and Fejzic et al (“Crosslinks Between Human Leukocyte Antigen DRB1*01 and Human Leukocyte Antigen DRB1*13 Allelic Variants and Occurrence of Rheumatoid Arthritis in Patients From Federation of Bosnia and Herzegovina”. Arch Rheumatology. 2017, 32(4), pages 290-297). as applied to claims 1, 5-7, 9, 11 and 1-17 above, and further in view of Traish et al (Journal of Clinical Medicine, 2018, 7, 549, pages 1-33).
The cited US 2016/0281165 (Goldring et al), Vasudevan and Fejzic as above.
With regard to prevention or treatment of for ALTR or ARMD the cited US 2016/0281165 (Goldring et al) teaches and/or suggests a generic compound that could modulate immune response of patients with inflammatory diseases.
As applied to claim 18, the cited US 2016/0281165 (Goldring et al) does not teach administration of testosterone. But testosterone therapy in well knonw in patients with inflammatory diseases (see Traish at introduction) including RA patients (see Traish at page 8, last paragraph). The RA patients are particularly affected by reaction to implants comprising metals as taught by Vasudevan.
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to administer testosterone to patients with inflammatory diseases or at risk of inflammation as result of immune reaction to debris of metal implants because testosterone therapy in well knonw in patients with inflammatory diseases including RA patients who are particularly affected by reaction to implants comprising metals .
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Claim Rejections - 35 USC § 101
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.
Claims 1, 5-7, 9 and 11 as amended remain/are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
Claims recite an assay which is a natural phenomenon and/or based on a natural phenomenon such as a natural presence of natural markers in body fluids of subjects who are predisposed to natural inflammatory response to metal implants or condition such as ALTR, ARMD or ALAVAL. The claimed methods of detecting makers in body fluids are routine and conventional practice. Evaluation of marker measurements or determining whether the subject has the detected markers as claimed is considered to be a mental step (abstract idea). The population under diagnosis is a general unlimited population since any and all will (might) have a metal implant in future.
This, this judicial exception is not integrated into a practical application because claimed elements in combination do not add a meaningful limitation or extra-solution to the claimed process.
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because when considered separately and in combination, they do not add significantly more (also known as an “inventive concept”) to the exception.
Response to Arguments
Applicant's arguments filed on 10/07/2025 have been fully considered but they are not all found persuasive.
The rejection of claims under 35 U.S.C. 102 (a) (1) as being anticipated by Giamperti et al (Case Reports in Orthopedics. 2016, article ID 8682737, pages 1-7) has been withdrawn in view of amendment to the claims and arguments drawn to detecting specific and/or particular claim-recited markers.
The rejection of claims under 35 U.S.C. 102 (a) (1) as being anticipated by US 2016/0281165 (Goldring et al) has been withdrawn in view of amendment to the claims and arguments drawn to detecting specific and/or particular claim-recited markers.
With regard to claim rejection under 35 U.S.C. 103 as being unpatentable over US 2016/0281165 (Goldring et al), Vasudevan and Fejzic Applicants argue that the combined teaching of the cited refences would not suggest one of skill in the art to select the claim-recited specific HLA-DQ markers for monitoring subjects who has or will have a metal-containing metal resulting in ARMD or ALVAL.
This argument is not found persuasive because the cited 2016/0281165 (Goldring et al) clearly teaches that adverse local tissue reaction (ALTR) or immune response to implant would lead to implant failure (par. 0013) and the cited diagnosis method comprises detection of immune response associated markers including HLA-DQ markers (table 4, page 19). The secondary references provide evidence that HLA-DQ markers including the claim-1-recited specific markers are associated with rheumatoid arthritis (RA) and patients with RA are predisposed to ALTR (the cited Fejzic and Vasudevan respectively).
With regard to claim rejection under 35 U.S.C. 101 Applicants argue that claims are limited to detection of specific markers in a sample from a subject who has an implant or will have an implant without correlation to any disease. Thus, Applicants appear to argue that claims are not directed to a mental step or to an abstract idea.
However, claims recite an assay which is a natural phenomenon for being based on a natural phenomenon such as a natural presence of natural markers in body fluids of any and all subjects. The detection of makers in body fluids is a routine and conventional practice. The population under diagnosis is a general unlimited population since any and all will (might) have a metal implant in future and immune response to the implant as a natural event or phenomenon. Thus, clamed method as a whole is a simple observation of a natural phenomenon without significantly more or extra-solution.
No claims are allowed.
Conclusion
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.
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Vera Afremova
January 29, 2026
/VERA AFREMOVA/ Primary Examiner, Art Unit 1653