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 .
Information Disclosure Statement
The information disclosure statement filed January 13, 2025 is acknowledged and has been considered by the examiner.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The specification is objected to for the following reason:
The use of the term OSTEOSENSE®, which is a trade name or a mark used in commerce, has been noted in this application in [0031]. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
Claim 5 is objected to because of the following informalities:
Claim 5 recites a list of HAP-selective fluorescent dye options. The options within the list are separated by commas. However, there is no comma between tetracycline and chlortetracycline (the first two options in the list). In view of the disclosure as a whole, it appears that these are meant to be distinct options in the claimed list. Therefore, there should be a comma between these options.
Appropriate correction is 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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-11 and 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson (WO 2018/039030 A1) in view of Atmeh (Atmeh, A. R.; et al., J. Microscopy, 2015 – provided by Applicant in IDS filed January 13, 2025) and Palczewska (Palczewska, G.; et al., JCI Insight, 2018).
Thompson teaches a method of using hydroxyapatite-selective fluorescent dyes in combination with fluorescence lifetime imaging to detect hydroxyapatite deposits in retina tissue and predict or detect age-related macular degeneration (Title and Abstract). More specifically, Thompson teaches a method comprising administering a hydroxyapatite-selective fluorescent dye to the retina tissue in an amount sufficient for binding to hydroxyapatite deposits or spherules in retina tissue to form a HAP/dye complex, irradiating the HAP/dye complex with electromagnetic radiation to excite the HAP/dye complex, and monitoring and/or measuring the lifetime of a fluorescent signal (pg. 3, [0010]). Thompson teaches that the lifetime of the fluorescent signal may be measured or monitored by a fluorescence lifetime imaging device employing time and frequency domain technologies (pg. 3, [0011]). Thompson further teaches that the HAP-selective fluorescent dye is preferably a tetracycline (pg. 4, [0013]). Thompson teaches that the method may be used to detect HAP deposits in retina tissue and that the method may involve scanning a tissue, obtaining a profile, and using the profile to diagnose or predict age-related macular degeneration and/or Alzheimer’s disease in a subject (pg. 4-5, [0014]). Thompson teaches specific examples of the use of doxycycline and chlortetracycline to perform FLIM in retinal tissue using an excitation wavelength of 443 nm (pg. 15-16, [0064]-[0065]). Thompson teaches that fluorescence lifetime imaging is advantageous because it helps overcome the challenge of overlapping emission spectra of fluorophores and endogenous molecules in tissue (pg. 11, [0044]). Thompson teaches that fluorescence lifetime imaging is compatible with two-photon excitation microscopy (pg. 11, [0043]). Thompson also teaches that HAP is a mineral form of calcium phosphate and can be found in bones and teeth (pg. 9, [0037]).
Thompson does not teach exciting the HAP/fluorescent dye complex with electromagnetic radiation at a wavelength in a range from about 700 nm to about 1 mm.
Atmeh teaches two-photon fluorescence microscopy in combination with tetracycline labeling (pg. 151, Summary). More specifically, Atmeh teaches the use of a calcium silicate cement to remineralize dentine dental tissue (pg. 151, Summary; and pg. 152, left column, last paragraph). Atmeh teaches labeling the dental tissue with tetracycline and describes tetracycline as a mineralization labeling fluorophore (pg. 152, left column, paragraphs 3-5). Atmeh teaches that tetracycline labelling shows a preference for calcium phosphate products (pg. 155, left column). Atmeh teaches using the tetracycline label to perform two photon excitation fluorescence imaging (pg. 155, Figure 3) and fluorescence lifetime measurements (pg. 154, Figure 2). Atmeh also teaches that two-photon fluorescence allows for deep tissue imaging with high resolution and reduces the scattering of the exciting radiation (pg. 152, left column, third paragraph).
Palczewska teaches a method of using two-photon fluorescence imaging of retinal tissue (pg. 1, Abstract). Specifically, Palczewska teaches performing two-photon imaging using 20, 32, or 75 femtosecond pulses at 740 nm or variable wavelengths in the IR spectrum on a mouse eye in vivo (pg. 14, third paragraph; pg. 3, Figure 1; and pg. 4, Figure 2). Palczewska also teaches using the two-photon imaging for fluorescence lifetime imaging (pg. 15, paragraph 5; and pg. 11, Figure 9). Palczewska teaches that two-photon excitation fluorescence imaging of eye tissue with infrared light is advantageous because the IR light is scattered less by the ocular tissue compared to visible light (pg. 2, second paragraph). Palczewska also teaches that two-photon excitation minimizes out-of-focus noise (pg. 2, second paragraph). Palczewska also teaches that shorter wavelengths, such as those shorter than 400 nm, have poor transmission through a human eye, while longer wavelengths, such as IR wavelengths, have better transmission (pg. 2, second paragraph). Palczewska teaches that two-photon excitation fluorescence imaging can be performed either with or without artificial fluorescent markers (pg. 10, last paragraph) and discloses that two-photon FLIM has been done with exogenous fluorophores in living mice (pg. 11, paragraph 3).
A person of ordinary skill in the art would have recognized that both Thompson and Atmeh teach performing fluorescence imaging and fluorescence lifetime measurements with tetracycline bound to calcium phosphate minerals. It would also be recognized that both Thompson and Palczewska teach fluorescent lifetime imaging of retina tissue. It would be further recognized that both Atmeh and Palczewska teach two-photon excitation fluorescence methods.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the tetracycline fluorescence lifetime hydroxyapatite imaging method of Thompson by using two photon excitation fluorescence as taught by Atmeh and Palczewska because Palczewska teaches that two photon excitation is useful for imaging retinal tissue due to reduced out-of-focus noise and improved transmission through tissue (MPEP § 2134(I)(G)). This would predictably result in a method of imaging HAP deposits in tissue comprising administering a HAP-selective dye to form HAP/dye complexes, exciting the dye with an electromagnetic radiation wavelength from about 700 nm to 1 mm, and measuring fluorescence lifetime signal of the HAP/dye complex.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Palczewska teaches that two photon excitation fluorescence can be performed in retina tissue and states that such methods can be done with or without exogenous dyes and because Atmeh teaches that mineral-bound tetracycline can be used in two photon excitation fluorescence methods.
The skilled artisan would have been motivated to make this modification because Palczewska teaches that two photon excitation is useful for imaging retinal tissue due to reduced out-of-focus noise and improved transmission through tissue and because Atmeh teaches that two photon fluorescence microscopy allows for deep tissue imaging with high resolution.
Regarding claim 1, Thompson teaches a method of detecting HAP deposits in retina tissue of a subject comprising administering a tetracycline derivative to a subject in an amount sufficient for binding of the tetracycline derivative to any HAP deposits in the tissue of the subject, exciting the HAP/tetracycline complex, and monitoring and/or measuring the fluorescence lifetime of a fluorescent signal of any HAP/tetracycline derivative complex (pg. 4-5, [0014]). Thompson also teaches that the method involves obtaining a profile of HAP deposits in the tissue wherein the HAP/tetracycline complex exhibits a longer fluorescence lifetime signal than background tissue (pg. 5, [0014]). Thompson teaches that tetracycline, tetracyclines, and tetracycline derivatives are hydroxyapatite-selective fluorescent dyes (pg. 4, [0013]). Thompson teaches that HAP is a calcium phosphate mineral (pg. 9, [0037]). Additionally, Atmeh teaches performing two photon excitation fluorescence imaging with tetracycline bound to calcium phosphate minerals (pg. 155, Figure 3). Atmeh specifically teaches performing the two-photon excitation with an excitation electromagnetic radiation wavelength of 800 nm (pg. 152, right column, second paragraph). As 800 nm is within the claimed range of about 700 nm to about 1 mm, it renders the claimed range obvious (MPEP § 2144.05(I)). Additionally, Palczewska teaches the use of 740 nm (pg. 14, second paragraph) and 790 nm (pg. 5, Figure 3) irradiation for two photon excitation fluorescence in retina tissue. Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 1 obvious.
Regarding claim 2, Atmeh teaches performing the two-photon excitation of tetracycline-calcium phosphate complexes with an excitation electromagnetic radiation wavelength of 800 nm (pg. 152, right column, second paragraph). As 800 nm is within the claimed range of about 700 nm to about 2500 nm, it renders the claimed range obvious (MPEP § 2144.05(I)). Additionally, Palczewska teaches the use of 740 nm (pg. 14, second paragraph) and 790 nm (pg. 5, Figure 3) irradiation for two photon excitation fluorescence in retina tissue. Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 2 obvious.
Regarding claims 3 and 4, Atmeh teaches using two photon excitation to irradiate the tetracycline-calcium phosphate complexes to perform fluorescence (pg. 152, right column, second paragraph; and pg. 155, Figure 3). Additionally, Palczewska teaches the use of two photon excitation to perform fluorescence lifetime imaging in retina tissue (pg. 11, Figure 9). The examiner interprets two photon excitation to be a specific form of multiphoton excitation, as two photons is more than one and is thus multiple photons being used to excite the dye. Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claims 3 and 4 obvious.
Regarding claims 5 and 6, Thompson teaches that the hydroxyapatite-selective fluorescent dye is preferably a tetracycline, including chlortetracycline and doxycycline (pg. 4, [0013]). Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claims 5 and 6 obvious.
Regarding claim 7, Thompson teaches that the hydroxyapatite-selective fluorescent dye may be administered orally, topically, or intravenously to detect retinal HAP deposits (pg. 4, [0013]). Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 7 obvious.
Regarding claim 8, Thompson teaches the use of chlortetracycline for fluorescence lifetime imaging and that the chlortetracycline-labeled HAP deposits in retina tissue exhibited a fluorescence lifetime of approximately 1.6 nsec. Thompson also teaches that the fluorescence lifetime of chlortetracycline bound to HAP is about 1.4 to 1.9 nsec (pg. 5, [0015]). Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 8 obvious.
Regarding claim 9, Thompson teaches that the fluorescence lifetime of doxycycline bound to HAP is 3.5 to 4.2 nsec. As this range overlaps with the claimed range, it renders the claimed range obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 9 obvious.
Regarding claim 10, Thompson teaches that the device used to perform the method preferably uses fluorescence lifetime imaging microscopy or fluorescence lifetime imaging ophthalmoscopy (pg. 14, [0052]). Additionally, Palczewska teaches the use of two photon excitation in fluorescence lifetime imaging microscopy in retinal tissue (pg. 11, Figure 9). Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 10 obvious.
Regarding claim 11, Palczewska teaches the use of excitation pulse durations of 20 fs, 32 fs, and 75 fs to perform two-photon excitation for in vivo imaging of retinal tissue (pg. 14, paragraph 3). The examiner interprets these to be femtosecond range pulse durations. Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 11 obvious.
Regarding claim 13, Thompson teaches that the fluorescence lifetime measurement can be done using time-domain or frequency-domain methods (pg. 3, [0011]). Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 13 obvious.
Regarding claim 14, Thompson teaches that the method of imaging HAP deposits can include scanning the retina tissue of the subject with a fluorescence lifetime imaging device (pg. 4, [0013]). Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 14 obvious.
Regarding claim 15, Thompson teaches that the method of imaging HAP deposits can include obtaining a profile of HAP deposits in the subject’s retina tissue wherein the HAP deposits bound to the tetracycline derivative exhibits a longer lifetime compared to background tissue (pg. 4-5, [0014]). Thompson teaches that tetracycline derivatives are a hydroxyapatite-specific fluorescent dye (pg. 4, [0013]). Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 15 obvious.
Regarding claim 16, Thompson teaches that the obtained profile of HAP deposits can be used to diagnose or predict age-related macular degeneration and/or Alzheimer’s disease in the subject (pg. 4-5, [0014]). Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 16 obvious.
Regarding claim 17, Thompson teaches that the method of administering a tetracycline derivative to retina tissue to complex with HAP, exciting the HAP/dye complex, and measuring fluorescence lifetime can be used in diagnosing or predicting the likelihood of having or developing age-related macular degeneration and/or Alzheimer’s disease (pg. 6, [0018]). Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 17 obvious.
Regarding claim 18, Thompson teaches that the method is for the detection of HAP spherules or deposits in the retina of a subject (pg. 2, [0009]). Additionally, Palczewska teaches that two photon excitation can be used for fluorescence lifetime imaging microscopy in retina tissue (pg. 11, Figure 9). Therefore, the combined teachings of Thompson, Atmeh, and Palczewska render claim 18 obvious.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Thompson, Atmeh, and Palczewska, as applied to claims 1-11 and 13-18 above, and further in view of Kezic (Kezic, J. M.; et al., Arthritis & Rheumatism, 2011).
As described above, the combined teachings of Thompson, Atmeh, and Palczewska teach a method of labeling HAP deposits in retina tissue in a subject comprising administering a hydroxyapatite-specific fluorescent dye (including tetracyclines) to a subject in an amount sufficient for the dye to form a complex with HAP, exciting the HAP/dye complex with electromagnetic radiation at a wavelength in a range from about 700 nm to about 1 mm, and measuring fluorescence lifetime of the HAP/dye complex. Furthermore, Thompson teaches that the HAP-binding dye may be systemically administered by intravenous injection and that the dye may be combined with appropriate pharmaceutically acceptable carrier, adjuvants, and/or excipients for the delivery method (pg. 14, [0054]). Thompson also teaches that hydroxyapatite-selective fluorescent dyes include OSTEOSENSE 680EX® (pg. 4, [0013]).
The combined teachings of Thompson, Atmeh, and Palczewska do not explicitly teach performing imaging with the fluorescence lifetime imaging device about 8 hours to about 72 hours after administration of the fluorescent dye.
Kezic teaches a murine mouse model of uveitis that coincides with arthritis and spondylitis (pg. 762, Title and Abstract). More specifically, Kezic teaches imaging microcalcification and bone remodeling using a NIR fluorescent dye, OSTEOSENSE 680® (pg. 764, right column, second paragraph; and pg. 768, Figure 5). Kezic teaches that the dye was administered by intravenous injection and fluorescence imaging was performed 24 hours after administration (pg. 764, right column, second paragraph).
A person of ordinary skill in the art would have recognized that the OSTEOSENSE dye taught by Kezic is a hydroxyapatite-binding dye, as evidenced by Thompson. Thus, it would be recognized that both Thompson and Kezic teach fluorescence-based imaging methods using hydroxyapatite binding dyes in subjects.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the tetracycline fluorescence lifetime hydroxyapatite imaging method of the combination of Thompson, Atmeh, and Palczewska by performing the fluorescence imaging of the subject at 24 hours after administration of the dye as taught by Kezic because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions (MPEP § 2143(I)(A)). This would predictably result in a method of imaging HAP deposits in tissue comprising performing the imaging 24 hours after administering a HAP-selective dye.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Kezic teaches imaging 24 hours after administration successfully enables fluorescence detection of HAP-binding fluorophores. There would also be a reasonable expectation of success because Thompson describes tetracyclines and OSTEOSENSE® as alternative dyes for the same purpose.
The skilled artisan would have been motivated to make this modification because imaging at a time after administration enables time for absorption of the dye into retina tissue and provides time for the dye to bind to hydroxyapatite in the tissue and for non-specific binding to be cleared.
Regarding claim 12, as described above, the combined teachings of Thompson, Atmeh, and Palczewska render the method of claim 1 obvious. Furthermore, Thompson teaches that the HAP-binding dye may be systemically administered by intravenous injection and that the dye may be combined with appropriate pharmaceutically acceptable carrier, adjuvants, and/or excipients for the delivery method (pg. 14, [0054]). The examiner interprets this to read on administering a pharmaceutical composition comprising the HAP-selective fluorescent dye. Additionally, Kezic teaches performing NIR fluorescence imaging using the dye OSTEOSENSE 680®, wherein a solution of the dye is administered by intravenous injection and fluorescence imaging was performed 24 hours after administration (pg. 764, right column, second paragraph; and pg. 768, Figure 5). As evidenced by Thompson, OSTEOSENSE® is a hydroxyapatite-selective fluorescent dye (pg. 4, [0013]). As described above, the combined method of Thompson, Atmeh, Palczewska, and Kezic would be a method in which a pharmaceutical composition comprising a HAP-selective fluorescent dye is administered and imaging with the fluorescence lifetime imaging device would occur 24 hours subsequent to said administration. As 24 hours is within the range of about 8 hours to about 72 hours, it renders the claimed range obvious (MPEP § 2144.05((I)). Therefore, the combined teachings of Thompson, Atmeh, Palczewska, and Kezic render claim 12 obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7, 10-11, and 13-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11,253,614 in view of Atmeh (Atmeh, A. R.; et al., J. Microscopy, 2015 – provided by Applicant in IDS filed January 13, 2025) and Palczewska (Palczewska, G.; et al., JCI Insight, 2018).
The claims of the ‘614 patent are drawn to a method for predicting or diagnosing age-related macular degeneration and/or Alzheimer’s disease in a subject by detecting hydroxyapatite deposits in retina tissue. The method comprises administering a tetracycline derivative to a subject in an amount sufficient for binding to a HAP deposit in the tissue, exciting the tetracycline derivative by irradiation of the tissue with electromagnetic radiation, obtaining a profile of HAP deposits in the subject wherein the HAP/dye complex exhibits a longer fluorescence lifetime compared to the fluorescence lifetime of background tissue, and using the obtained profile to diagnose or predict age-related macular degeneration and/or Alzheimer’s disease in the subject.
The claims of the ‘614 patent are not drawn to a method of using electromagnetic radiation of wavelengths from about 700 nm to about 1 mm or use of multiphoton excitation.
As described above, Atmeh teaches two-photon fluorescence microscopy in combination with tetracycline labeling (pg. 151, Summary). More specifically, Atmeh teaches the use of a calcium silicate cement to remineralize dentine dental tissue (pg. 151, Summary; and pg. 152, left column, last paragraph). Atmeh teaches labeling the dental tissue with tetracycline and describes tetracycline as a mineralization labeling fluorophore (pg. 152, left column, paragraphs 3-5). Atmeh teaches that tetracycline labelling shows a preference for calcium phosphate products (pg. 155, left column). Atmeh teaches using the tetracycline label to perform two photon excitation fluorescence imaging (pg. 155, Figure 3) and fluorescence lifetime measurements (pg. 154, Figure 2). Atmeh also teaches that two-photon fluorescence allows for deep tissue imaging with high resolution and reduces the scattering of the exciting radiation (pg. 152, left column, third paragraph).
As described above, Palczewska teaches a method of using two-photon fluorescence imaging of retinal tissue (pg. 1, Abstract). Specifically, Palczewska teaches performing two-photon imaging using 20, 32, or 75 femtosecond pulses at 740 nm or variable wavelengths in the IR spectrum on a mouse eye in vivo (pg. 14, third paragraph; pg. 3, Figure 1; and pg. 4, Figure 2). Palczewska also teaches using the two-photon imaging for fluorescence lifetime imaging (pg. 15, paragraph 5; and pg. 11, Figure 9). Palczewska teaches that two-photon excitation fluorescence imaging of eye tissue with infrared light is advantageous because the IR light is scattered less by the ocular tissue compared to visible light (pg. 2, second paragraph). Palczewska also teaches that two-photon excitation minimizes out-of-focus noise (pg. 2, second paragraph). Palczewska also teaches that shorter wavelengths, such as those shorter than 400 nm, have poor transmission through a human eye, while longer wavelengths, such as IR wavelengths, have better transmission (pg. 2, second paragraph). Palczewska teaches that two-photon excitation fluorescence imaging can be performed either with or without artificial fluorescent markers (pg. 10, last paragraph) and discloses that two-photon FLIM has been done with exogenous fluorophores in living mice (pg. 11, paragraph 3).
A person of ordinary skill in the art would have recognized that both the ‘614 patent claims and Atmeh teach performing fluorescence imaging and fluorescence lifetime measurements with tetracycline bound to calcium phosphate minerals. It would also be recognized that both the ‘614 patent claims and Palczewska teach fluorescent lifetime imaging of retina tissue. It would be further recognized that both Atmeh and Palczewska teach two-photon excitation fluorescence methods.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the tetracycline fluorescence lifetime hydroxyapatite imaging method claimed by the ‘614 patent by using two photon excitation fluorescence as taught by Atmeh and Palczewska because Palczewska teaches that two photon excitation is useful for imaging retinal tissue due to reduced out-of-focus noise and improved transmission through tissue (MPEP § 2134(I)(G)). This would predictably result in a method of imaging HAP deposits in tissue comprising administering a HAP-selective dye to form HAP/dye complexes, exciting the dye with an electromagnetic radiation wavelength from about 700 nm to 1 mm, and measuring fluorescence lifetime signal of the HAP/dye complex.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Palczewska teaches that two photon excitation fluorescence can be performed in retina tissue and states that such methods can be done with or without exogenous dyes and because Atmeh teaches that mineral-bound tetracycline can be used in two photon excitation fluorescence methods.
The skilled artisan would have been motivated to make this modification because Palczewska teaches that two photon excitation is useful for imaging retinal tissue due to reduced out-of-focus noise and improved transmission through tissue and because Atmeh teaches that two photon fluorescence microscopy allows for deep tissue imaging with high resolution.
Regarding instant claim 1, conflicting claim 1 of the ‘614 patent is drawn to a method of detecting HAP deposits in retina tissue in a subject comprising administering a tetracycline derivative to the subject in an amount sufficient for binding to any HAP deposits in the tissue, exciting the HAP/dye complex with electromagnetic radiation, and monitoring lifetime of a fluorescent signal of a HAP/dye complex wherein the complex exhibits a longer fluorescence lifetime compared to the fluorescence lifetime of the background tissue. Additionally, Atmeh teaches performing two photon excitation fluorescence imaging with tetracycline bound to calcium phosphate minerals (pg. 155, Figure 3). Atmeh specifically teaches performing the two-photon excitation with an excitation electromagnetic radiation wavelength of 800 nm (pg. 152, right column, second paragraph). As 800 nm is within the claimed range of about 700 nm to about 1 mm, it renders the claimed range obvious (MPEP § 2144.05(I)). Additionally, Palczewska teaches the use of 740 nm (pg. 14, second paragraph) and 790 nm (pg. 5, Figure 3) irradiation for two photon excitation fluorescence in retina tissue.
Regarding instant claim 2, Atmeh teaches performing the two-photon excitation of tetracycline-calcium phosphate complexes with an excitation electromagnetic radiation wavelength of 800 nm (pg. 152, right column, second paragraph). As 800 nm is within the claimed range of about 700 nm to about 2500 nm, it renders the claimed range obvious (MPEP § 2144.05(I)). Additionally, Palczewska teaches the use of 740 nm (pg. 14, second paragraph) and 790 nm (pg. 5, Figure 3) irradiation for two photon excitation fluorescence in retina tissue.
Regarding instant claims 3 and 4, Atmeh teaches using two photon excitation to irradiate the tetracycline-calcium phosphate complexes to perform fluorescence (pg. 152, right column, second paragraph; and pg. 155, Figure 3). Additionally, Palczewska teaches the use of two photon excitation to perform fluorescence lifetime imaging in retina tissue (pg. 11, Figure 9). The examiner interprets two photon excitation to be a specific form of multiphoton excitation, as two photons is more than one and is thus multiple photons being used to excite the dye.
Regarding instant claims 5 and 6, conflicting claim 1 of the ‘614 patent teaches that the tetracycline derivative is selected from the group consisting of chlortetracycline, demeclocycline, doxycycline, methacycline, anhydrochlortetracycline, anhydrotetracycline, and chelocardin.
Regarding instant claim 7, conflicting claim 6 of the ‘614 patent teaches that the tetracycline derivative may be administered topically, orally, or by injection.
Regarding instant claim 10, conflicting claim 1 of the ‘614 patent teaches the use of a fluorescence lifetime imaging device to scan retina tissue of a subject. Additionally, Palczewska teaches the use of two photon excitation in fluorescence lifetime imaging microscopy in retinal tissue (pg. 11, Figure 9).
Regarding instant claim 11, Palczewska teaches the use of excitation pulse durations of 20 fs, 32 fs, and 75 fs to perform two-photon excitation for in vivo imaging of retinal tissue (pg. 14, paragraph 3). The examiner interprets these to be femtosecond range pulse durations.
Regarding instant claim 13, conflicting claim 4 of the ‘614 patent is drawn to a method in which the fluorescence lifetime imaging device uses frequency-domain technology.
Regarding instant claim 14, conflicting claim 1 of the ‘614 patent is drawn to a method including scanning the tissue of a subject with a fluorescence lifetime imaging device.
Regarding instant claim 15, conflicting claim 1 of the ‘614 patent is drawn to a method including obtaining a profile of HAP deposits in a subject wherein the HAP deposits bound to the tetracycline dye exhibit a longer fluorescence lifetime compared to background tissue.
Regarding instant claim 16, conflicting claim 1 of the ‘614 patent is drawn to a method wherein the obtained profile is used to diagnose or predict age-related macular degeneration and/or Alzheimer’s disease in the subject.
Regarding instant claim 17, conflicting claim 1 of the ‘614 patent is drawn to a method of diagnosing or predicting age-related macular degeneration and/or Alzheimer’s disease in a subject.
Regarding instant claim 18, conflicting claim 1 of the ‘614 patent is drawn to a method of imaging retina tissue in a subject.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric P Mosher whose telephone number is (571)272-3258. The examiner can normally be reached Monday-Friday 9am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached at (571) 272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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