Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Claims 45-54 are pending and under consideration in the instant office action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 49-54 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method for treating the fluid accumulation associated with lymphedema comprising administering to a subject exhibiting lymphedema that results from occlusion of lymph vessels, a nucleic acid encoding HGF, wherein said nucleic acid encoding HGF is administered to and expressed at the site of lymphedema, resulting in a decrease in the fluid associated with said edema and an increase in the number of lymphatic vessels, does not reasonably provide enablement for treatment wherein the HGF is not expressed at the site of lymphedema or where lymphedema the result of some cause other than occlusion of the lymphatic vessels. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/ or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The invention is drawn to treatment of lymphedema by administering a nucleic acid encoding HGF. The claims do not require that HGF protein be expressed from the vector, indicating that the nucleic acid itself could be therapeutic.
The specification teaches surgical induction of lymphedema by ligation of lymph vessels in the tail. Lymph accumulated at the tail and was observable as a fluid swelling. Administration of a nucleic acid encoding human HGF at the site of the lymphedema was found to decrease the fluid and increase the number of lymph vessels in the area.
The specification also fails to teach treatment of other causes of the lymphedema other than occlusion of the lymph vessels. For example, lymphedema resulting from parasitic infection that leads to abnormal transport function would presumably affect transport function in newly formed lymph vessels (see Alitalo, 2002, page 221; IDS), precluding the treatment effect provided by new lymph vessels.
The claims fail to require that HGF protein be produced from the administered nucleic acid. The specification fails to support a direct effect of the nucleic acid on symptoms of lymphedema.
Because the Specification fails to support other causes of lymphedema such as infection or causes that would also be present in new lymphatic vessels and the Specification does not support that the nucleic acid alone would treat lymphedema, it would require undue experimentation for the skilled artisan to carry out the invention as currently claimed.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claim 45-54 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over USPGPUB 2007/0010443 (Detmar), which claims priority to US Provisional 60/667,463, filed 03/31/2005 and Kondo (2004, JACC, 44:644-653). The earliest effective filing date for the instant application is 07/28/2005, the filing date of JP2005219410.
Claim 45 is drawn to a method of treating lymphedema by administering a nucleic acid encoding HGF. Claim 45 recites limitations including preparation of a vector, determining a human is in need of treatment and injecting a naked plasmid vector into a muscle at the site of lymphedema where the vector comprises the nucleotide sequence of SEQ ID NO:5.
Detmar teaches treatment of secondary lymphedema (paragraph 0005, acquired post-surgery or post-radiation, claim 52) using a nucleic acid encoding HGF (see paragraphs 5 and 6 and claims 14-16). Detmar teaches SEQ ID NO:1 encoding HGF, which is the same protein set forth in SEQ ID NO:2 of the instant application and is the cDNA inserted into the pVAX1 vector to make SEQ ID NO:5. Detmar discusses administration of treatment agents by IM injection (paragraphs 95 and 103). Detmar teaches treatment of humans as well as non-humans (claim 47).
Detmar did not teach the pVAX1 vector that flanks the cDNA encoding HGF (SEQ ID NO:1) to make SEQ ID NO:5. However, SEQ ID NO:5 is an expression vector comprising the human HGF gene inserted into the multi-cloning site of the pVAX1 vector. Kondo taught administering naked pVAX1 vector containing HGF to a rat model of acute MI. Insertion of the nucleic acid encoding HGF (SEQ ID NO:1 of Detmar) into the pVAX vector as taught by Kondo, leads to a plasmid vector consisting of the nucleotide sequence set forth by SEQ ID NO:5. Kondo taught administration of 1.5 mg of the claimed vector led to increased angiogenesis. While Kondo treated myocardial infarction as opposed to lymphedema, both are treated by HGF-induced angiogenesis.
In sum, Detmar showed that HGF has a positive, active effect on lymphangiogenesis while Kondo showed that it also has a positive, active effect on angiogenesis. While the systems are separate, both are formed with positive growth effects of the growth factor, HGF, on endothelial cells. HGF was shown to induce formation of both lymph and blood vessels when delivered to a site of occlusion.
It would have been obvious at the time of filing to combine the method of treating lymphedema using a nucleic acid encoding HGF (SEQ 1 of Detmar which is inserted into the pVAX1 vector to make SEQ ID NO:5) with those of Kondo teaching insertion of coding sequence into pVAX1 (the vector of SEQ ID NO:5) to result in treatment of lymphedema with SEQ ID NO:5 as claimed. One would have been motivated to make such a combination as the pVAX1 vector was well-known in its use in mammalian gene therapy and Kondo used the naked vector to increase angiogenesis to treat a myocardial occlusion as opposed to the claimed lymphatic occlusion and the vector comprises the constitutive CMV promoter to provide general expression of the inserted transgene. In the instant case, it is accepted that generation of the recited vector is done applying a known techniques to a known method to form an expression vector with predictable results. There is no indication from applicants that the particulars of the instant vector is an advancement over the art that was achieved with unexpected consequences or otherwise unexpected results. One would have had a reasonable expectation of success in carrying out the combined method as gene therapy using pVAX1 vectors was well-known and well-utilized at the time of filing. The instant claimed SEQ ID NO:5 is the sequence resulting from insertion of the HGF cDNA of SEQ IDNO:1, taught by Detmar, into the BamHI and NotI sites of the multi-cloning site of pVAX1 which is standard practice with no inventive measure.
With regard to the dosage amount (claims 48-49), Kondo taught enhancing angiogenesis by administration of 1.5 mg of plasmid at the site of desired angiogenesis. Claims 50 and 51 narrow the dosage range to 3-mg and 2-4 mg, respectively. These ranges would be obvious given the teachings of Kondo as Kondo used a rat model and adjusting the dosage in a different species (human) would have been obvious. Routine optimization is not considered inventive and no evidence has been presented that use 2-3 mg (as opposed to 1.5 mg) was other than routine, that the dosage and effect resulting from the optimization would have any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art.
With regard to claims 53 and 54, requiring the lymphedema be caused by surgery to treat cancer, the source of the lymphedema does not appear to alter the lymphedema itself and the limitations are not limitations to the method steps. It would be obvious to use the method that leads to neovascularization to clear lymphedema of any source. The cause of lymphedema by removal of a lymph node or tumor would be considered similar to that caused by occlusion.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached on M-F 6AM-2:30PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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