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 .
Continued Examination Under 37 CFR 1.114A
Request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/16/2026 has been entered.
Withdrawn Rejections
Applicants' arguments/remarks filed 01/16/2026 are acknowledged:
The rejection of Claims 51 as dependent on the rejection of independent claim 1 under 35 USC 103 has been withdrawn in view of the amendment of the claim.
The rejection of Claims 1-3, 5, 9-10, 22, 26, 27, 28, 33, 43, 57, 71, 88 and 93-98 under 35 U.S.C. 103 as being unpatentable over Dor and Nichamin has been withdrawn.
The Terminal Disclaimers to Obviate a Double Patenting Rejection over Prior Patents No. 10/500,183, 10/709,135 and 11/446,241, filed 01/16/2026 are acknowledged. The Double Patenting Rejection has been withdrawn.
Status of Application
Applicants' arguments/remarks filed 01/16/2026 are acknowledged. Claims10 and 51 are currently amended. Claim 99 is newly added. Claims 1-3, 5, 9-10, 22, 26-28, 33, 43, 51, 57, 71, 88 and 93-99 are examined on the merits within and are currently pending.
Modified Rejections
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.
Claim(s) 1-3 and 5, 9-10, 22, 26, 27, 28, 33, 43, 57, 71, 88, 93-98 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dor et al. (US 8,663,639 B2) in view of Li et al. (CN 103025829 A) and Nichamin (US 20130331768 A1).
Claims 1-3, 5, 9-10, and 57
Dor et al. teach a method for treating an ocular disease in a human subject. The method comprising administering periocularly to the subject a volume of formulation comprising an amount of therapeutic agent and a volume of an excipient, wherein the amount of therapeutic agent is sufficient to treat the ocular disease. (Col. 8, lines 22-27). In some variations, the liquid formulation is administered topically. (Col. 6, lines 50-51). Therapeutic agents include one of acetylcholinesterase inhibitors (col 25, lines 29 and 54) demecarium bromide (col. 27, line 48). Periocular means surrounding the eyeball but within the orbit. The periocular region includes the eyelids, eyelashes, eyebrows, eye shape, skin texture, and tear duct.
Dor et al. do not teach acetylcholinesterase inhibitors inactivate are mite growth and specifically demodex brevis and/or demodex folliculorum mites’ growth.
Li et al. teach active ingredients of insecticides can be used as acetylcholinesterase inhibitors, mite growth inhibitors. (0060).
Nichamin teaches the present invention pertains to methods and kits for treating and preventing eye and body conditions and for cleaning eye area tissue. (0003). One of the causes of facial and/or ocular rosacea are the presence of Demodex folliculorum or Demodex brevis on the skin of the face and/or eyelid as possible causes or triggers for rosacea. (0009). Ocular rosacea is a condition that affects the eyelids and ocular surface, causes inflammatory eye disease that can cause blepharitis and, conjunctivitis (inflammation or infection of the conjunctiva that lines the eyelid and part of the eyeball). It causes irritation, dryness, redness in the eyes, grittiness in the eyes, and/or blurry vision. (0006).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat an ocular disease in a human subject, comprising administering to the subject a volume of formulation comprising an amount of therapeutic agent and a volume of an excipient, sufficient to treat the ocular disease, by administered topically therapeutic agents that include one of acetylcholinesterase inhibitors demecarium bromide, taught by Dor et al., acetylcholinesterase inhibitors can inhibit mite growth, taught by Li et al. and methods for treating and preventing eye, facial and/or eyelid ocular rosacea causes or triggers by the presence of Demodex folliculorum or Demodex brevis, inflammatory eye disease that can cause blepharitis, conjunctivitis, inflammation or infection of the conjunctiva that lines the eyelid and part of the eyeball, irritation, dryness, redness in the eyes, grittiness in the eyes, and/or blurry vision, lid margin and conjunctival telangiectasias (appearance of blood vessels near the surface), taught by Nichamin since they have provided the method of treatment.
With regard to claims 22, 26, 94, and 96, Dor et al. teach liquid formulations which deliver a variety of therapeutic agents, to a subject for an extended period of time; liquid formulations which form a non-dispersed mass when placed in an aqueous medium of a subject; non-dispersed mass forming liquid formulations which form a gel or gel-like substance in an aqueous medium; liquid formulations, comprising a therapeutic agent and a plurality of polymers; and methods for delivering therapeutic agents to a subject for an extended period of time using the liquid formulations. The liquid formulation may be placed in an aqueous medium of a subject, including but not limited to via intraocular or periocular administration, or placement proximate to a site of a disease or condition to be treated in a subject. (Abs). The formulation consists of about 0.001% w/w to about 10% w/w of the therapeutic agent. (Col 15, lines 9-10). It is customary to use the least amount of insecticide for the purpose; one of ordinary skill in the art would seek to minimize the amount of acetylcholinesterase inhibitor for this reason.
With regard to claim 27, Dor et al. teach the formulations for use may also include gel formulations, erodible and nonerodable polymers, microspheres, and liposomes. (Col 77, lines 16-17).
With regard to claim 28, Dor et al. teach a method for treating an ocular disease in a human subject. The method comprising administering periocularly to the subject a volume of formulation comprising an amount of therapeutic agent and a volume of an excipient, wherein the amount of therapeutic agent is sufficient to treat the ocular disease. (Col. 8, lines 22-27).Therapeutic agents include one of acetylcholinesterase inhibitors (col 25, lines 29 and 54) demecarium bromide (col. 27, line 48). Periocular means surrounding the eyeball but within the orbit. The periocular region includes the eyelids, eyelashes, eyebrows, eye shape, skin texture, and tear duct.
With regard to claim 33, Dor et al. teach the method comprising administering periocularly to the subject a volume of formulation comprising an amount of therapeutic agent and a volume of an excipient, wherein the amount of therapeutic agent is sufficient to treat the ocular disease. (Col. 8, lines 22-27). In some variations, the liquid formulation is administered topically. (Col. 6, lines 50-51). Therapeutic agents include one of acetylcholinesterase inhibitors (col 25, lines 29 and 54) demecarium bromide (col. 27, line 48). Periocular means surrounding the eyeball but within the orbit. The periocular region includes the eyelids, eyelashes, eyebrows, eye shape, skin texture, and tear duct.
For treatment, prevention, inhibition, delaying the onset of, or causing the regression of certain diseases or conditions, it may be desirable to maintain delivery of a therapeutically
effective amount of the therapeutic agent for an extended period of time. Depending on the disease or condition being treated, prevented, inhibited, having onset delayed, or being
caused to regress this extended period of time may be at least about 2 weeks, at least about 3 months. (Col 103, lines 9-18).
The optimal dosage regime will depend on the therapeutic amount of the therapeutic agent needing to be delivered, and the period over which it need be delivered. (Col 103, lines 39-40).
Depending on the therapeutic agent being delivered and/or the diseases and conditions
being treated, prevented, inhibited, onset delayed, and regression caused this period of delay before delivery of the therapeutic agent commences may be about 1 hour, about 6 hours,
about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 21 days, about 28 days, about 35 days, or about 42 days. Other delay periods may be possible. Delayed release formulations that may be used are known to people versed in the technology. (Col 103, lines 55-67).
With regard to claim 43, Dor et al. teach a method for treating an ocular disease in a human subject. The method comprising administering periocularly to the subject a volume of formulation comprising an amount of therapeutic agent and a volume of an excipient, wherein the amount of therapeutic agent is sufficient to treat the ocular disease. (Col. 8, lines 22-27). In some variations, the liquid formulation is administered topically. (Col. 6, lines 50-51). Therapeutic agents include one of acetylcholinesterase inhibitors (col 25, lines 29 and 54) demecarium bromide (col. 27, line 48). Periocular means surrounding the eyeball but within the orbit. The periocular region includes the eyelids, eyelashes, eyebrows, eye shape, skin texture, and tear duct.
Nichamin teaches the present invention pertains to methods and kits for treating and preventing eye and body conditions and for cleaning eye area tissue. (0003). One of the cause(s) of facial and/or ocular rosacea are the presence of Demodex folliculorum or Demodex brevis on the skin of the face and/or eyelid as possible causes or triggers for rosacea. (0009).
With regard to claim 57, this method is not patentably distinct from clam 1; the same reasoning that applies to claim 1 would apply to this claim as well.
With regard to claim 71, Dor et al. teach the ocular disease is selected from the group consisting of dry eye, conjunctivitis (col 17, line 34, 36).
With regard to claim 88, Dor et al. teach the liquid formulations may comprise a solution, suspension, an in-situ gelling formulation, or an emulsion. The droplets in the
emulsion may generally be of any size. (Col. 6, lines 57-60).
With regard to claim 93, Dor et al. teach a method for treating an ocular disease in a human subject. The method comprising administering periocularly to the subject a volume of formulation comprising an amount of therapeutic agent and a volume of an excipient, wherein the amount of therapeutic agent is sufficient to treat the ocular disease. (Col. 8, lines 22-27). The periocular area is the region of the face that surrounds the eye, including the eyelids, eyelashes, eyebrows, tear duct, and skin.
With regard to claim 95, Dor et al. teach the liquid formulations comprising a solvent consisting of dimethyl sulfoxide (DMSO). (Col 20, lines 55-57).
With regard to claim 96, Dor et al. teach in some variations, the liquid formulation is administered topically. (Col. 6, lines 50-51). Liquid formulations which form a non-dispersed mass when placed in an aqueous medium of a subject; non-dispersed mass forming liquid formulations which form a gel or gel-like substance in an aqueous medium; liquid formulations, comprising a therapeutic agent and a plurality of polymers; and methods for delivering therapeutic agents to a subject for an extended period of time using the liquid formulations. The liquid formulation may be placed in an aqueous medium of a subject, including but not limited to via intraocular or periocular administration, or placement proximate to a site of a disease or condition to be treated in a subject. (Abs). Other therapeutic agents that may be used include cyclosporine (Col 27, line 22)
With regard to claim 97, Dor et al. teach Other therapeutic agents that may be used include anti-inflammatory agents, including, but not limited to nonsteroidal anti-inflammatory agents and steroidal anti-inflammatory agents. (Col. 26, line 15-18).
With regard to claim 98, Dor et al. teach Diseases and conditions associated with tissues of the body, including but not limited to tissues in the eye, can be effectively treated, prevented, inhibited, onset delayed, or regression caused by administering therapeutic agents to those tissues. (Abs). The method comprising administering periocularly to the subject a volume of formulation comprising an amount of therapeutic agent and a volume of an excipient, wherein the amount of therapeutic agent is sufficient to treat the ocular disease. (Col. 8, lines 22-27). In some variations, the liquid formulation is administered topically. (Col. 6, lines 50-51). Therapeutic agents include one of acetylcholinesterase inhibitors (col 25, lines 29 and 54) demecarium bromide (col. 27, line 48).
With regard to claim 99, Dor et al. teach that the amount of therapeutic agent is sufficient to treat the disease or condition. One specific example of an amount is at column 118, line 66 which states that the formulation contained 880 µg of rapamycin. Assuming a body weight of 180 lb or about 82 kg, that would be 0.88 mg/82 kg or 0.01 mg/kg. One of ordinary skill in the art would have found it obvious to determine the appropriate dosage given this guidance, as well as other guidance throughout the reference, to use a dosage in the claimed range.
Response to Arguments
Regarding 35 USC 103 rejection
Dor’s reference:
Applicant argues that the Office acknowledges that Dor is deficient with respect to teaching "the formulation is to inactivate demodex brevis and/or demodex folliculorum mites." To address this fundamental deficiency in Dor, the Office relies on Nichamin "for treating and preventing eye and body conditions and for cleaning eye area tissue." Office Action at p. 3 (citing para [0003] of Nichamin).
Applicant's arguments have been fully considered and they are not persuasive since the basis for 103 rejection is that no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things.
Applicant argues that the Office is engaging in unfair hindsight reconstruction with respect to the allegation that Dor teaches a therapeutic agent "include one of acetylcholinesterase inhibitors (col 25, lines 29 and 54) demecarium bromide (col. 27, line 48)." Office Action at p.3. It is important to understand that those selections of therapeutic agents come out of a list of therapeutic agents spanning columns 25-32 of Dor. See, e.g.
Applicant's arguments have been fully considered and they are not persuasive since it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that the attached Declaration establishes there is uncertainty around whether compounds can kill mites, specifically for acetylcholinesterase inhibitors (See attached
Declaration providing evidence that 6/22 (27%) tested acetylcholinesterase inhibitors
(including one inactive that is derivative of an acetylcholinesterase inhibitor but is more
broadly recognized as a blood thinner) are not miticidal. A single compound in a large generic disclosure does not render that compound inherently disclosed or obvious, unless there is motivation or direction toward it. As discussed below, the secondary cited reference Nichamin does not fairly provide that motivation or direction. And Applicant emphasizes the claimed invention is directed to compounds that inhibit acetylcholinesterase inside Demodex mites (since claim 1 states "inactivate ... mites"), not the human enzyme acetylcholinesterase. This is what the
Demodex assay demonstrates, the mechanism of killing action on the isolated Demodex
mite ex vivo.
Applicant's arguments have been fully considered and they are persuasive according to previous office action, since Dor teaches treating an ocular disease in a human subject, with sufficient amount of therapeutic agent, to administer topically, and teach the compound demecarium bromide as one of acetylcholinesterase inhibitors, still there was no link to the killing, inactivating or inhibiting mite growth. As a result, Claim 99, with applicant limitation of specific concentration, is allowed since there is not prior art for that. However, this modified office action, the argument is not persuasive, even with a single compound in the list, taught by Dor, since the rejection of claim 1 is modified by adding Li’s teaching that acetylcholinesterase inhibitor can inhibit mite growth and if so, it can inhibit growth of specific mites taught by Nichamin, even though the effective concentrations may be different for different mites and even Dor and Li do not teach the specific results applicant recites in the Declaration, 6/22, still one with skill in the art can learn the ideas to test and find out. "A reference is presumed operable until applicant provides facts rebutting the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980)". And Nichamin teaches of specific mites Demodex folliculorum or Demodex brevis. One with skill in the art could learn from Dor, Li and Nichamin and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things.
Nichamin reference:
Applicant argues that Nichamin to allege Demodex folliculorum or Demodex brevis is "One of the causes of facial and/or ocular rosacea." Importantly, however, para [0009] of Nichamin is an explicit admission that it was unknown whether those mites are a cause of "facial and/or ocular rosacea." See Nichamin at para [0009]: Applicant acknowledges Nichamin teaches killing mites, including at para [0053]: "The treatment may work to agitate or move unwanted material such as Oemodex eggs, larva or mites and remove them from the eyelash follicle or other part of the eye or eyelid, or to make them accessible to the oil. The dermabrasive may also eliminate organisms by direct killing or damage."
Applicant's arguments have been fully considered and they are not persuasive because these points facial and/or ocular rosacea, or Oemodex eggs, larva or mites applicant pointing out above are not in the claim’s limitation. As mentioned above that prior arts may teach more and may teach different things.
Applicant argues that Nichamin does not teach using anti-cholinesterase inhibitors to do mite killing.
This argument is explained in the response to Dor’s teaching above that the basis for 103 rejection is that no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things. Anti-cholinesterase inhibitors are taught by Dor. Anti-cholinesterase inhibitors to kill mites are taught by Li. And Specific mites are taught by Nichamin.
Applicant argues that without any rational explanation, somehow the Office decides to select "demecarium bromide" out of all the compounds in Dor to arrive at the instant invention. But Nichamin does not teach use of acetylcholinesterase inhibitors. As discussed above, Dor does not specifically teach use of demecarium bromide (or any acetylcholinesterase inhibitors). This is a clear impermissible hindsight reconstruction where the only motivation to select the acetylcholinesterase inhibitor of Dor comes not from Nichamin, but rather from Applicant's own invention.
Applicant's arguments have been fully considered and they are not persuasive because again Dor teaching the acetylcholinesterase inhibitors with a list of compounds. Li teaches acetylcholinesterase inhibitors can kill mites. And Nichamin teaches the specific mites Demodex brevis and Demodex folliculorum mites. The ideas are already taught. One with skill in the art can carry out tests for themselves and to find out specific drugs with specific concentrations to kill specific mites. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that the instant claims are directed to specifically enumerated acetylcholinesterase inhibitors. This reflects the fact that not all acetylcholinesterase inhibitors have Demodex-killing activity. See attached Declaration at Points 8-9. Accordingly, even if the Office continues to allege that the combination of Dor and Nichamin makes obvious use of an acetylcholinesterase inhibitor to treat ophthalmological afflictions, there is no fair teaching as to selecting the instantly recited species of acetylcholinesterase inhibitors to "inactivate demodex brevis and/or demodex folliculorum mites from said eye region". Again, this is important because Applicant has experimentally confirmed that many acetylcholinesterase inhibitors do not inactivate demodex brevis and/or demodex folliculorum (see attached Declaration at Point 9).
Applicant's arguments have been fully considered and they are persuasive according to previous office action, however are not persuasive according to this modified rejection because Dor teaching the acetylcholinesterase inhibitors with a list of compounds. Li teaches acetylcholinesterase inhibitors can kill mites. And Nichamin teaches the specific mites Demodex brevis and Demodex folliculorum mites. The ideas are already taught. One with skill in the art can carry out tests for themselves and to find out specific drugs with specific concentrations to kill specific mites.
Claim 51 is allowed as it is amended to be an independent claim without prior art to be rejected and since it is not dependent on rejected claim 1.
Conclusion
Claim 51 is allowed. Claims 1-3, 5, 9-10, 22, 26-28, 33, 43, 57, 71, 88 and 93-99 are not allowed.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615